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Primary cancer cells exert unique capacity to disseminate and nestle in distant organs. Once seeded in secondary sites, cancer cells may enter a dormant state, becoming resistant to current treatment approaches, and they remain silent until they reactivate and cause overt metastases. To illuminate the complex mechanisms of cancer dormancy, 10 transcriptomic datasets from the literature enabling 21 dormancy-cancer comparisons were mapped on protein-protein interaction networks and gene-regulatory networks to extract subnetworks that are enriched in significantly deregulated genes. The genes appearing in the subnetworks and significantly upregulated in dormancy with respect to proliferative state were scored and filtered across all comparisons, leading to a dormancy-interaction network for the first time in the literature, which includes 139 genes and 1974 interactions. The dormancy interaction network will contribute to the elucidation of cellular mechanisms orchestrating cancer dormancy, paving the way for improvements in the diagnosis and treatment of metastatic cancer., Scientific and Technological Research Council of Turkey (TÜBİTAK)

Breast cancer (BC) remains a clinical challenge despite improved treatments and public awareness to ensure early diagnosis. A major issue is the ability of BC cells (BCCs) to survive as dormant cancer cells in the bone marrow (BM), resulting in the cancer surviving for decades with the potential to resurge as metastatic cancer. The experimental evidence indicates similarity between dormant BCCs and other stem cells, resulting in the preponderance of data to show dormant BCCs being cancer stem cells (CSCs). The BM niche and their secretome support BCC dormancy. Lacking in the literature is a comprehensive research to describe how the hypoxic environment within the BM may influence the behavior of BCCs. This information is relevant to understand the prognosis of BC in young and aged individuals whose oxygen levels differ in BM. This review discusses the changing information on vascularity in different regions of the BM and the impact on endogenous hematopoietic stem cells (HSCs). This review highlights the necessary information to provide insights on vascularity of different BM regions on the behavior of BCCs, in particular a dormant phase. For instance, how the transcription factor HIF1-α (hypoxia-inducible factor 1 alpha), functioning as first responder under hypoxic conditions, affects the expression of specific gene networks involved in energy metabolism, cell survival, tumor invasion and angiogenesis. This enables cell fate transition and facilitates tumor heterogeneity, which in turn favors tumor progression and resistance to anticancer treatments Thus, HIF1-α could be a potential target for cancer treatment. This review describes epigenetic mechanisms involved in hypoxic responses during cancer dormancy in the bone marrow. The varied hypoxic environment in the BM is relevant to understand the complex process of the aging bone marrow for insights on breast cancer outcome between the young and aged.

Breast cancer cells (BCCs) can remain dormant at the metastatic site, which when revoked leads to formation of metastasis several years after the treatment of primary tumor. Particularly, awakening of dormant BCCs in the brain results in breast cancer brain metastasis (BCBrM) which marks the most advanced stage of the disease with a median survival period of ~4–16 months. However, our understanding of dormancy associated with BCBrM remains obscure, in part, due to the lack of relevant in vitro platforms to model dormancy associated with BCBrM. To address this need, we developed an in vitro hyaluronic acid (HA) hydrogel platform to model dormancy in brain metastatic BCCs via exploiting the bio-physical cues provided by HA hydrogels while bracketing the normal brain and metastatic brain malignancy relevant stiffness range. In this system, we observed that MDA-MB-231Br and BT474Br3 brain metastatic BCCs exhibited a dormant phenotype when cultured on soft (0.4 kPa) HA hydrogel compared to stiff (4.5 kPa) HA hydrogel as characterized by significantly lower EdU and Ki67 positivity. Further, we demonstrated the nuclear localization of p21 and p27 (markers associated with dormancy) in dormant MDA-MB-231Br cells contrary to their cytoplasmic localization in the proliferative population. We also demonstrated that the stiffness-based dormancy in MDA-MB-231Br cells was reversible and was, in part, mediated by focal adhesion kinases and the initial cell seeding density. Finally, RNA sequencing confirmed the dormant phenotype in MDA-MB-231Br cells. This platform could further our understanding of dormancy in BCBrM and could be adapted for anti-metastatic drug screening. Statement of Significance Our understanding of dormancy associated with BCBrM remains obscure, in part, due to the lack of relevant in vitro platforms to model dormancy associated with BCBrM. Herein, we present a HA hydrogel-based platform to model dormancy in brain metastatic BCCs while recapitulating key aspects of brain microenvironment. We demonstrated that the biophysical cues provided the HA hydrogel mediates dormancy in brain metastatic BCCs by assessing both proliferation and cell cycle arrest markers. We also established the role of focal adhesion kinases and initial cell seeding density in the stiffness-mediated dormancy in brain metastatic BCCs. Further, RNA-seq. confirmed the dormant phenotype in brain metastatic BCCs. This platform could be utilized to further our understanding of microenvironmental regulation of dormancy in BCBrM.

Progress in cancer therapies has resulted in improved survival of patients with early stage breast cancer. However, mortality remains high in patients with distant recurrence of the disease after initially successful treatment of early stage breast cancer. To this end, tumor recurrences have been attributed to the presence of dormant tumor cells in breast cancer patients and cancer survivors. Current clinical practice guidelines recommend a “wait and watch” approach for tumor recurrence. This is because of our limited understanding of tumor dormancy. Dormant tumor cells are quiescent, and thus, do not respond to chemotherapies or radiation therapies, and they are not operable. Therefore, immunotherapy is the only option for the treatment of tumor dormancy. However, gaps in our knowledge as to dormancy-specific antigens prevent a relapse preventing vaccine design. Here, we provide a critical review of cancer immunotherapy, and discuss empirical evidence related to naturally-occurring tumor dormancy and treatment-induced tumor dormancy at the site of primary tumor and in distant organs before and after cancer therapies. Finally, we suggest that personalized vaccines targeting dormancy-associated neoantigens, which can be given to patients with early stage disease after the completion of neoadjuvant therapies and tumor resection as well as to cancer survivors could eliminate relapse causing dormant cells and offer a cure for cancer.

Emphasizing the dynamic processes between cancer and host immune system, the initially discovered concept of cancer immunosurveillance has been replaced by the current concept of cancer immunoediting consisting of three phases: elimination, equilibrium, and escape. Solid tumors composed of both cancer and host stromal cells are an example of how the three phases of cancer immunoediting functionally evolve, and how a tumor shaped by the host immune system gets a finally resistant phenotype. Elimination, equilibrium, and escape are described in this chapter in detail, including the role of immune surveillance, cancer dormancy, disruption of the antigen-presenting machinery, tumor-infiltrating immune cells, and resistance to apoptosis, as well as the function of tumor stroma, microvesicles, exosomes and inflammation.

Simple Summary In this perspective article we discuss the importance of investigating the role of the ECM on tumor metastasis and tumor dormancy. First, we discuss the importance of the ECM in cancer progression. Then, we revise the parallelisms between dormant cells and stem cells and the role of the ECM in stem cell regulation. Finally, we comment on the evidence describing the role of the ECM in tumor dormancy and highlight key outstanding questions in the tumor dormancy field. Abstract While most primary tumors can be effectively treated, therapeutics fail to efficiently eliminate metastases. Metastases arise from cancer cells that leave the primary tumor and seed distant sites. Recent studies have shown that cancer cells disseminate early during tumor progression and can remain dormant for years before they resume growth. In these metastatic organs, cancer cells reside in microenvironments where they interact with other cells, but also with the extracellular matrix (ECM). The ECM was long considered to be an inert, non-cellular component of tissues, providing their architecture. However, in recent years, a growing body of evidence has shown that the ECM is a key driver of cancer progression, and it can exert effects on tumor cells, regulating their metastatic fate. ECM remodeling and degradation is required for the early steps of the metastatic cascade: invasion, tumor intravasation, and extravasation. Similarly, ECM molecules have been shown to be important for metastatic outgrowth. However, the role of ECM molecules on tumor dormancy and their contribution to the dormancy-supportive niches is not well understood. In this perspective article, we will summarize the current knowledge of ECM and its role in tumor metastasis and dormancy. We will discuss how a better understanding of the individual components of the ECM niche and their roles mediating the dormant state of disseminated tumor cells (DTCs) will advance the development of new therapies to target dormant cells and prevent metastasis outgrowth.

Background Cancer metastasis is a complex process involving the spread of malignant cells from a primary tumor to distal organs. Understanding this cascade at a mechanistic level could provide critical new insights into the disease and potentially reveal new avenues for treatment. Transcriptome profiling of spontaneous cancer models is an attractive method to examine the dynamic changes accompanying tumor cell spread. However, such studies are complicated by the underlying heterogeneity of the cell types involved. The purpose of this study was to examine the transcriptomes of metastatic breast cancer cells using the well-established MMTV-PyMT mouse model. Methods Organ-derived metastatic cell lines were harvested from 10 female MMTV-PyMT mice. Cancer cells were isolated and sorted based on the expression of CD44low/EpCAMhigh or CD44high/EpCAMhigh surface markers. RNA from each cell line was extracted and sequenced using the NextSeq 500 Illumina platform. Tissue-specific genes were compared across the different metastatic and primary tumor samples. Reads were mapped to the mouse genome using STAR, and gene expression was quantified using RSEM. Single-cell RNA-seq (scRNA-seq) was performed on select samples using the ddSeq platform by BioRad and analyzed using Seurat v3.2.3. Monocle2 was used to infer pseudo-time progression. Results Comparison of RNA sequencing data across all cell populations produced distinct gene clusters. Differential gene expression patterns related to CD44 expression, organ tropism, and immunomodulatory signatures were observed. scRNA-seq identified expression profiles based on tissue-dependent niches and clonal heterogeneity. These cohorts of data were narrowed down to identify subsets of genes with high expression and known metastatic propensity. Dot plot analyses further revealed clusters expressing cancer stem cell and cancer dormancy markers. Changes in relevant genes were investigated across pseudo-time and tissue origin using Monocle2. These data revealed transcriptomes that may contribute to sub-clonal evolution and treatment evasion during cancer progression. Conclusions We performed a comprehensive transcriptome analysis of tumor heterogeneity and organ tropism during breast cancer metastasis. These data add to our understanding of metastatic progression and highlight targets for breast cancer treatment. These markers could also be used to image the impact of tumor heterogeneity on metastases.

Stem cells including cancer stem cells (CSC) divide symmetrically or asymmetrically. Usually symmetric cell division makes two daughter cells of the same fate, either as stem cells or more differentiated progenies; while asymmetric cell division (ACD) produces daughter cells of different fates. In this review, we first provide an overview of ACD, and then discuss more molecular details of ACD using the well- characterized Drosophila neuroblast system as an example. Aiming to explore the connections between cell heterogeneity in cancers and the critical need of ACD for self-renewal and generating cell diversity, we then examine how cell division symmetry control impacts common features associated with CSCs, including niche competition, cancer dormancy, drug resistance, epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET), and cancer stem cell plasticity. As CSC may underlie resistance to therapy and cancer metastasis, understanding how cell division mode is selected and executed in these cells will provide possible strategies to target CSC.

Cancer stem cells (CSCs) refer to a certain subpopulation within the tumor entity that is characterized by restricted cellular proliferation and multipotent differentiation potency. The existence of CSCs has been proven to contribute to the heterogeneity of malignancies, accounting for intensified tumorigenesis, treatment resistance, and metastatic spread. Dormancy was proposed as a reversible state of cancer cells that are temporarily arrested in the cell cycle, possessing several hallmarks that facilitate their survival within a devastating niche. This transient period is evoked to enter an actively proliferating state by multiple regulatory alterations, and one of the most significant and complex factors comes from local and systemic inflammatory reactions and immune components. Although CSCs and dormant cancer cells share several similarities, the clear relationship between these two concepts remains unclear. Thus, the detailed mechanism of immune cells interacting with CSCs and dormant cancer cells also warrants elucidation for prevention of cancer relapse and metastasis. In this review, we summarize recent findings and prospective studies on CSCs and cancer dormancy to conclude the relationship between these two concepts. Furthermore, we aim to outline the mechanism of immune components in interfering with CSCs and dormant cancer cells to provide a theoretical basis for the prevention of relapse and metastasis.

The paradigm of the Somatic Mutation Theory (SMT) is failing, and a new paradigm is underway but not yet established. What is being challenged is a conceptual approach that involves the entire human biology and the development of chronic diseases. The behavior of breast and other solid cancers is compatible with the concept that the primary tumor is able to control its microscopic metastases, in the same way that an organ (e.g., the liver) is able to control its physiological size. This finding suggested that cancer and its metastases may behave as an organoid. The new paradigm under construction considers the origin of tumors as a disturbance in the communication network between tissue cell populations and between cells and extracellular matrix, and supports a systemic approach to the study of both healthy and pathologic tissues. The commentary provides a rationale for the role of physical exercise in the control of tumor dormancy according to a human evolutionary perspective.

Dormancy is an inactive period of an organism’s life cycle that permits it to survive through phases of unfavorable conditions in highly variable environments. Dormancy is not binary. There is a continuum of dormancy phenotypes that represent some degree of reduced metabolic activity (hypometabolism), reduced feeding, and reduced reproduction or proliferation. Similarly, normal cells and cancer cells exhibit a range of states from quiescence to long-term dormancy that permit survival in adverse environmental conditions. In contrast to organismal dormancy, which entails a reduction in metabolism, dormancy in cells (both normal and cancer) is primarily characterized by lack of cell division. “Cancer dormancy” also describes a state characterized by growth stagnation, which could arise from cells that are not necessarily hypometabolic or non-proliferative. This inconsistent terminology leads to confusion and imprecision that impedes progress in interdisciplinary research between ecologists and cancer biologists. In this paper, we draw parallels and contrasts between dormancy in cancer and other ecosystems in nature, and discuss the potential for studies in cancer to provide novel insights into the evolutionary ecology of dormancy.

Metastasis and relapse account for the great majority of cancer-related deaths. Most metastatic lesions are micro metastases that have the capacity to remain in a non-dividing state called “dormancy” for months or even years. Commonly used anticancer drugs generally target actively dividing cancer cells. Therefore, cancer cells that remain in a dormant state evade conventional therapies and contribute to cancer recurrence. Cellular and molecular mechanisms of cancer dormancy are not fully understood. Recent studies indicate that a major cellular stress response mechanism, autophagy, plays an important role in the adaptation, survival and reactivation of dormant cells. In this review article, we will summarize accumulating knowledge about cellular and molecular mechanisms of cancer dormancy, and discuss the role and importance of autophagy in this context.

In the bone marrow (BM) microenvironment, where breast cancer (BC)-disseminated tumor cells (DTCs) can remain dormant for decades, NG2+/Nestin+ mesenchymal stem cells (MSCs) promote hematopoietic stem cell quiescence. Here we reveal that periarteriolar BM-resident NG2+/Nestin+ MSCs can also instruct BC DTCs to enter dormancy. NG2+/Nestin+ MSCs produce transforming growth factor (TGF)-β2 and bone morphogenetic protein (BMP)7 and activate a quiescence pathway dependent on TGFBRIII and BMPRII, which via p38-kinase, results in p27 induction. Genetic depletion of MSCs or conditional knockout of TGF-β2 in MSCs using an NG2-CreER driver led to bone metastatic outgrowth of otherwise dormant p27+/Ki67− DTCs. Also, patients with estrogen receptor-positive BC without systemic recurrence displayed higher frequency of TGF-β2 and BMP7 detection in the BM. Our results provide direct proof that hematopoietic stem cell dormancy niches control BC DTC dormancy and suggest that aging or extrinsic factors that affect the NG2+/Nestin+ MSC niche homeostasis may result in a break from dormancy and BC bone relapse. Aguirre-Ghiso and colleagues report that bone-marrow-resident mesenchymal stem cells promote cancer dormancy through TGF-β family members.

Recurrent disease after prolonged cancer dormancy is a major cause of cancer associated mortality, yet many of the mechanisms that are engaged to initiate dormancy as well as later recurrence remain incompletely understood. It is known that cancer cells initiate adaptation mechanisms to adapt tightly regulated cellular processes to non-optimal growth environments; Recent investigations have begun to elucidate the contribution of these mechanisms to malignant progression, with intriguing studies now defining cellular stress as a key contributor to the development and maintenance of cancer dormancy. This review will focus on our current understanding of stress responses facilitating malignant cell adaptation and metabolic reprogramming to establish cancer dormancy.

The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment1–3. These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative. Here we show that different tissue-specific microenvironments restrain or allow the progression of breast cancer in the liver—a frequent site of metastasis4 that is often associated with a poor prognosis5. Using mouse models, we show that there is a selective increase in natural killer (NK) cells in the dormant milieu. Adjuvant interleukin-15-based immunotherapy ensures an abundant pool of NK cells that sustains dormancy through interferon-γ signalling, thereby preventing hepatic metastases and prolonging survival. Exit from dormancy follows a marked contraction of the NK cell compartment and the concurrent accumulation of activated hepatic stellate cells (aHSCs). Our proteomics studies on liver co-cultures implicate the aHSC-secreted chemokine CXCL12 in the induction of NK cell quiescence through its cognate receptor CXCR4. CXCL12 expression and aHSC abundance are closely correlated in patients with liver metastases. Our data identify the interplay between NK cells and aHSCs as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing metastatic outgrowth. Liver-resident natural killer (NK) cells sustain the dormancy of disseminated breast cancer cells, and a decrease in NK cells and increase in activated hepatic stellate cells is associated with the formation of liver metastases.

Disseminated non-dividing (dormant) cancer cells as well as those in equilibrium with the immune response remain the major challenge for successful treatment of cancer. The equilibrium between disseminated dormant cancer cells and the immune system is reminiscent of states that can occur during infection or allogeneic tissue and cell transplantation. We discuss here the major competing models of how the immune system achieves a self nonself discrimination (pathogen/danger patterns, quorum, and coinhibition/tuning models), and suggest that taking advantage of a combination of the proposed mechanisms in each model may lead to increased efficacy in tackling cancer cell dormancy.

Lung cancer produces the highest mortality rate among cancers, mainly due to its late diagnosis accompanied by single or multiple organ metastasis to the lymph node, pleura, liver, brain and/or bones. In this chapter, we will review the major cellular signalling pathways that promote the proliferation and metastasis of lung cancer cells to each of these metastatic sites, hopefully to shine the light on the possible therapeutic targets that could be developed against these pathways for better therapeutic outcome. Cellular pathways including MAPK, CXCR4/CXCL12, ALK, Rho/ROCK, PI3K and RANK/RANKL signalling will be elaborated in relation to their roles in lymph node, pleura, liver, brain and bone metastasis of lung cancer, respectively. The blooming understanding of microRNA (miRNA) in lung cancer in these recent years has shown that it could play bi-faceted roles in modulating oncogenic pathways. Thus, we also briefly described the candidates of miRNA that may either promote or inhibit the key pathways in lung cancer with various metastatic sites.

Simple Summary Although testicular germ cell tumor (TGCT) carries a high cure rate, some patients still die from it. We investigated the genetic landscape and cellular origins of cancers that develop later in life after treatment for TGCT and found evidence that a common progenitor cell might be responsible for both. This study shows the possible importance of stem-like cells in the development of cancer. Abstract Although genetic changes may be pivotal in the origin of cancer, cellular context is paramount. This is particularly relevant in a progenitor germ cell tumor and its differentiated mature teratoma counterpart when it concerns tumor heterogeneity and cancer dormancy in subsequent second malignancies (subsequent malignant neoplasms (SMNs)). From our tumor registry database, we identified 655 testicular germ cell tumor (TGCT) patients who developed SMNs between January 1990 and September 2018. Of the 113 solid organ SMNs, 42 had sufficient tumor tissue available for fluorescence in situ hybridization (FISH) analysis of isochromosome 12p [i(12p)]. We identified seven additional patients for targeted DNA and RNA sequencing of teratomas and adjacent somatic transformation. Finally, we established cell lines from freshly resected post-chemotherapy teratomas and evaluated the cells for stemness expression by flow cytometry and by the formation of teratomas in a xenograft model. In our cohort, SMNs comprising non-germ cell tumors occurred about 18 years after a diagnosis of TGCT. Of the 42 SMNs examined, 5 (12%) contained i(12p) and 16 (38%) had 12p gain. When comparing a teratoma and adjacent somatic transformation, targeted DNA and RNA sequencing demonstrated high concordance. Studies of post-chemotherapy teratoma-derived cell lines revealed cancer-initiating cells expressing multipotency as well as early differentiation markers. For the first time, we demonstrated the prevalence of i(12p) in SMNs and the presence of progenitor cells embedded within mature teratomas after chemotherapy. Our findings suggest a progenitor stem-like cell of origin in SMN and TGCT and highlight the importance of cellular context in this disease.

Cancer cell dormancy is a common feature of human tumors and represents a major clinical barrier to the long-term efficacy of anticancer therapies. Dormant cancer cells, either in primary tumors or disseminated in secondary organs, may reawaken and relapse into a more aggressive disease. The mechanisms underpinning dormancy entry and exit strongly resemble those governing cancer cell stemness and include intrinsic and contextual cues. Cellular and molecular components of the tumor microenvironment persistently interact with cancer cells. This dialog is highly dynamic, as it evolves over time and space, strongly cooperates with intrinsic cell nets, and governs cancer cell features (like quiescence and stemness) and fate (survival and outgrowth). Therefore, there is a need for deeper insight into the biology of dormant cancer (stem) cells and the mechanisms regulating the equilibrium quiescence-versus-proliferation are vital in our pursuit of new therapeutic opportunities to prevent cancer from recurring. Here, we review and discuss microenvironmental regulations of cancer dormancy and its parallels with cancer stemness, and offer insights into the therapeutic strategies adopted to prevent a lethal recurrence, by either eradicating resident dormant cancer (stem) cells or maintaining them in a dormant state.

Cancer cell dormancy is a process whereby cells enter reversible cell cycle arrest, termed quiescence. Quiescence is essential for cancer cells to acquire additional mutations, to survive in a new environment and initiate metastasis, to become resistant to cancer therapy, and to evade immune destruction. Thus, dormant cancer cells are considered to be responsible for cancer progression. As we start to understand the mechanisms that enable quiescence, we can begin to develop pharmacological strategies to target dormant cancer cells. Herein, we summarize the major molecular mechanisms underlying the dormancy of disseminated tumor cells and drug-tolerant persister cells. We then analyze the current pharmacological strategies aimed (i) to keep cancer cells in the harmless dormant state, (ii) to reactivate dormant cells to increase their susceptibility to anti-proliferative drugs, and (iii) to eradicate dormant cancer cells.

BACKGROUND: Dormancy is one characteristic of cancer cells to make patients remain asymptomatic before metastasis and relapse, which is closely related to the survival rate of cancer patients, including head and neck squamous cell carcinoma (HNSCC). PRRX1 has previously been implicated in the invasion and metastasis of the epithelial-mesenchymal transition (EMT) process in different types of human carcinoma. However, whether PRRX1 can regulate cancer dormancy and its reactivation, leading to the migration and invasion of HNSCC cells, remains elusive. The aim of this study was to determine the role of PRRX1 in cellular phenotype plasticity and cancer dormancy of HNSCC cells and its association with miRNAs in HNSCC. METHODS: The expression of PRRX1 was detected by immunohistochemical staining in primary HNSCC samples and the metastatic lymph nodes. Meanwhile, the role of PRRX1 and its relationship with miR-642b-3p and EMT in cellular phenotype plasticity and cancer dormancy of HNSCC were investigated in vitro and in vivo. RESULTS: PRRX1 was significantly higher at the invasive front of HNSCC samples compared with the metastatic lymph nodes, and such switch process was accompanied by the cellular phenotype plasticity and cell dormancy activation. In HNSCC cell lines, PRRX1 positively promoted the expression of known EMT inducers and cooperated with activated TGF-β1 to contribute to EMT and migration and invasion of HNSCC cells. Then, we found that overexpression of miR-642b-3p, one of the most significantly downregulated miRNAs in PRRX1-overexpressed cells, significantly reduced the migration and invasion, and increased cell proliferation and apoptosis. And miR-642b-3p restoration reversed PRRX1-induced cell dormancy and EMT of HNSCC cells through TGF-β2 and p38. Finally, we demonstrated that overexpressed PRRX1 was closely correlated with miR-642b-3p downregulation and the upregulation of TGF-β2 and p38 in a xenograft model of HNSCC. CONCLUSIONS: Our findings showed that PRRX1 may be one of the main driving forces for the cellular phenotype plasticity and tumor dormancy of HNSCC. Therefore, we can raise the possibility that EMT may help to keep cancer cell in dormant state and mesenchymal-epithelial transition may resurge dormancy in HNSCC.

Graphical abstract, A better understanding of how microenvironmental factors regulate cancer dormancy is needed for development of new therapeutic strategies to control metastatic recurrence and disease progression. Modeling cancer dormancy using engineered, in vitro platforms is necessary for investigation under well-defined and well-controlled microenvironments. We present methods and protocols to fabricate, characterize, and implement engineered hydrogels with well-defined biochemical and physical properties for control over breast cancer cell phenotype in three-dimensional (3D) culture. Changes in hydrogel adhesivity, crosslink density, and degradability induce a range of phenotypic behaviors in breast cancer cells including: (1) high growth, (2) moderate growth, (3) single cell, restricted survival dormancy, and (4) balanced dormancy. We describe a method of classifying hydrogel formulations that support each of these phenotypic states. We also describe a method to phenotypically switch cancer cells from single cell dormancy to high growth by dynamically modulating ligand density, thereby recapitulating reactivation and metastatic recurrence.

International audience; Metastases and cancer recurrence are the main causes of cancer death. Circulating Tumor Cells (CTCs) and disseminated tumor cells are the drivers of cancer cell dissemination. The assessment of CTCs' clinical role in early metastasis prediction, diagnosis, and treatment requires more information about their biology, their roles in cancer dormancy, and immune evasion as well as in therapy resistance. Indeed, CTC functional and biochemical phenotypes have been only partially characterized using murine metastasis models and liquid biopsy in human patients. CTC detection, characterization, and enumeration represent a promising tool for tailoring the management of each patient with cancer. The comprehensive understanding of CTCs will provide more opportunities to determine their clinical utility. This review provides much-needed insights into this dynamic field of translational cancer research.

The secretome produced by cells within the bone marrow is significant to homeostasis. The bone marrow, a well-studied organ, has multiple niches with distinct roles for supporting stem cell functions. Thus, an understanding of mediators involved in the regulation of stem cells could serve as a model for clinical problems and solutions such as tissue repair and regeneration. The exosome secretome of bone marrow stem cells is a developing area of research with respect to the regenerative potential by bone marrow cell, particularly the mesenchymal stem cells. The bone marrow niche regulates endogenous processes such as hematopoiesis but could also support the survival of tumors such as facilitating the cancer stem cells to exist in dormancy for decades. The bone marrow-derived secretome will be critical to future development of therapeutic strategies for oncologic diseases, in addition to regenerative medicine. This article discusses the importance for parallel studies to determine how the same secretome may compromise safety during the use of stem cells in regenerative medicine.

Following efficient tumor therapy, some cancer cells may survive through a dormancy process, contributing to tumor recurrence and worse outcomes. Dormancy is considered a process where most cancer cells in a tumor cell population are quiescent with no, or only slow, proliferation. Recent advances indicate that redox mechanisms control the dormant cancer cell life cycle, including dormancy entrance, long-term dormancy, and metastatic relapse. This regulatory network is orchestrated mainly through redox modification on key regulators or global change of reactive oxygen species (ROS) levels in dormant cancer cells. Encouragingly, several strategies targeting redox signaling, including sleeping, awaking, or killing dormant cancer cells are currently under early clinical evaluation. However, the molecular mechanisms underlying redox control of the dormant cancer cell cycle are poorly understood and need further exploration. In this review, we discuss the underlying molecular basis of redox signaling in the cell life cycle of dormant cancer and the potential redox-based targeting strategies for eliminating dormant cancer cells.

Tumors undergo periods of dormancy followed by reactivation leading to metastatic disease. Arrest in the G0/G1 phase of the cell cycle and resistance to chemotherapeutic drugs are key hallmarks of dormant tumor cells. Here, we describe a 3D platform of bladder cancer cell dormancy and reactivation facilitated by a novel aminoglycoside-derived hydrogel, Amikagel. These 3D dormant tumor microenvironments (3D-DTMs) were arrested in the G0/G1 phase and were highly resistant to anti-proliferative drugs. Inhibition of targets in the cellular protein production machinery led to induction of endoplasmic reticulum (ER) stress and complete ablation of 3D-DTMs. Nanoparticle-mediated calcium delivery significantly accelerated ER stress-mediated 3D-DTM death. Transfer of 3D-DTMs onto weaker and adhesive Amikagels resulted in selective reactivation of a sub-population of N-cadherin deficient cells from dormancy. Whole-transcriptome analyses further indicated key biochemical differences between dormant and proliferative cancer cells. Taken together, our results indicate that 3D bladder cancer microenvironments of dormancy and reactivation can facilitate fundamental advances and novel drug discovery in cancer.

Cancer dormancy emerges when tumor cells cease to proliferate but remain alive in a quiescent state. Recent evidence suggests that cancer cells can stay dormant in a patient’s body for years before returning to a proliferative state, leading to cancer relapse. The lack of a system to efficiently identify and study dormant cancer cells is currently limiting further diagnostic and treatment developments to prevent cancer relapse. Herein, we present a novel encapsulation platform to identify and study dormancy-capable cancer cells in a quiescent state by inhibiting proliferation through physical confinement. The platform involves the encapsulation of cells within a stiff silica-PEG hydrogel produced by a sol–gel technique. Cells are immobilized in a nondegradable microenvironment where proliferation and movement are inhibited due to physical confinement of the gel. The platform was tested using non-cancerous cell lines HFF, HUVEC, Jurkat, MEF, and MCF-10A, and cancer cell lines LnCAP, MCF-7, MCF10DCIS.com , MDA-MB-468, and OVCAR-5. Viability and metabolic activity measurements showed that MCF-7, LnCAP, and MCF10DCIS.COM cells remained metabolically active for up to 3 weeks while non-cancerous lines and the rest of the cancer cell lines did not survive after a few days. Ki-67 immunofluorescent staining confirmed that surviving MCF-7 cells underwent cell cycle arrest as early as 48 hours after encapsulation. Furthermore, following extraction and recovery, these cells resumed proliferation, indicating that the induced cell cycle arrest was reversible. These results conclude that physically inhibiting proliferation via the silica-PEG hydrogel system can be used to identify cells that can enter a quiescent state, setting the groundwork for this platform to be explored as a cancer cell dormancy model.

Although surgical excision, chemo-, and radio-therapy are clearly advanced, tumors may relapse due to cells of the so-called "minimal residual disease". Indeed, small clusters of tumor cells persist in host tissues after treatment of the primary tumor elaborating strategies to survive and escape from immunological attacks before their relapse: this variable period of remission is known as "cancer dormancy". Therefore, it is crucial to understand and consider the major concepts addressing dormancy, to identify new targets and disclose potential clinical strategies. Here, we have particularly focused the relationships between tumor microenvironment and cancer dormancy, looking at a re-appreciated aspect of this compartment that is the low extracellular pH. Accumulating evidences indicate that acidity of tumor microenvironment is associated with a poor prognosis of tumor-bearing patients, stimulates a chemo- and radio-therapy resistant phenotype, and suppresses the tumoricidal activity of cytotoxic lymphocytes and natural killer cells, and all these aspects are useful for dormancy. Therefore, this review discusses the possibility that acidity of tumor microenvironment may provide a new, not previously suggested, adequate milieu for "dormancy" of tumor cells.

The challenge for treating breast cancer (BC) is partly due to long-term dormancy driven by formation of cancer stem cells (CSCs) capable of evading immune response and resist chemotherapy. BC cells (BCCs) show preference for bone marrow (BM), resulting in poor prognosis. CSCs utilize connexin 43 (Cx43) to form gap junctional intercellular communication (GJIC) with BM niche cells, fibroblasts and mesenchymal stem cells (MSCs). However, Cx43 is an unlikely target to reverse BC dormancy due to its role as hematopoietic regulator. We found N-cadherin (CDH2) and its associated pathways as potential drug targets. CDH2, highly expressed in CSCs, interacts intracellularly with Cx43, co-localizes with Cx43 in BCCs within BM biopsies of patients, and is required for Cx43-mediated GJIC with BM niche cells. Notably, CDH2-associated γ-secretase and pro-apoptotic pathways maintained BC dormancy. We thereby propose these pathways as potential pharmacological targets to prevent dormancy and chemosensitize resistant CSCs.

The genetic and environmental heterogeneity associated with tumors makes cancer treatment and recovery a difficult and unpredictable process. Patients with initially similar disease can experience vastly different outcomes including sustained recovery, refractory disease or, remarkably, recurrence years after treatment. Mathematical models informed with animal and human data provide tools for theoretical and clinical understanding of cancer progression and of the causes of highly variant disease outcomes. This work postulates a population balance model to describe how populations of a large ensemble of tumors of different sizes evolve in time. Each tumor can grow or reduce in size and metastasize. Gender-segregated, immune-competent and immune-suppressed translucent zebrafish (Casper variant) were inoculated with a transgenic melanoma cell line expressing human BRAF V600E and GFP and observed for tumor progression and metastasis. The model describes both these fish data sets, full histograms of population number vs size at multiple times for both immune states, and a human hepatocellular carcinoma data set also consisting of multiple time histograms very well with a minimum of cancer-specific parameters. The only zebrafish parameter to show strong gender-dependence was the host-dependent tumor reduction (immunity) parameter. This result significantly predicts that men should have far worse outcomes than females, yet similar metastasis rates, which are both indeed the case in human melanomas. Moreover the dynamic growth - reduction interplay, for certain relationships between these processes’ parameters in the model provides a potential mechanism for apparent cancer dormancy and recurrence. Although fish melanoma parameters are not in this range, the model guides future work to try to access it.

Immune-mediated dormancy is when the immune system keeps proliferating tumor cells unchanged, mostly via cytotoxic activity of immune cells. Cancer dormancy, especially immune-mediated dormancy, may be the explanation for tumor refractory and may be responsible for resistance to conventional chemo- and radiotherapies. Here, we will describe different scenarios as to how the immune cells and cytokines involved in cancer progression are connected with the initiation of dormancy and cancer treatment. Two distinct treatment methods, such as maintaining metastatic tumor cells dormant and awakening them, are also discussed. A better understanding of immune-mediated dormancy will help to design novel and effective immunotherapies and will likely increase the efficiency of tumor treatment inhibiting metastasis.

Pancreatic cancer (PC) is a highly lethal malignancy characterized by local tumor aggressiveness and early metastatic dissemination. While surgical resection is used to treat localized cancers, the majority of patients do recur suggesting the presence of disseminated tumor cells (DTC) at the time of surgery. These DTC's represent minimal residual disease. While most patients recur early, a subset recur late due to the reactivation of dormant tumor cells. Currently, the mechanisms of cancer dormancy are poorly understood in part due to a lack of animal models that reflect human disease. Here we describe a murine model of PC dormancy that mimics outcomes in resected human patients. Using single-cell transcriptomics and an assay for chromatin accessibility, we found dormancy is a distinct cellular state from pre or post-dormant cancer cells. Mechanisms of dormancy include increased expression of transcriptional repressor Dec2, which functionally drives quiescence, and monoallelic suppression of mutant KRAS by DNA methylation. Pathway analysis of dormant tumor cell transcriptomics indicated an up-regulation of enzymes involved in linoleic acid metabolism among others. Linoleic acid treatment of tumor cells resulted in inhibited cell proliferation, decreased tumor growth, and an increase in Dec2 expression. We have identified a dormancy gene signature that is distinct from non-dormant PC cells and found that this correlates with human resected patients with long term survivals, and inversely in patients with short term survivals. We demonstrate that dormancy is characterized by large scale transcriptomic changes and global chromatin remodeling. We developed methods for isolating DTCs from the livers of early stage PC patients undergoing resection. Using these methods we have found that the murine dormancy signature correlated with the gene expression of the DTCs and not primary tumor cells indicating this dormancy signature has human relevance with potential novel therapeutic avenues. Citation Format: Anthony S. Casabianca, Crissy Dudgeon, Chris Harris, Subhajyoto De, Mihir Shah, Arthur Roberts, Eric Collisson, Vinod Balachandran, Darren Carpizo. A genetic signature of cancer dormancy: implications for human disease derived from a novel murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 121.

CDH2 is required for connexin 43 (Cx43)–mediated gap junction intercellular communication between breast cancer cells and bone marrow niche cells to achieve dormancy and chemoresistance., The challenge for treating breast cancer (BC) is partly due to long-term dormancy driven by cancer stem cells (CSCs) capable of evading immune response and resist chemotherapy. BC cells show preference for the BM, resulting in poor prognosis. CSCs use connexin 43 (Cx43) to form gap junctional intercellular communication with BM niche cells, fibroblasts, and mesenchymal stem cells (MSCs). However, Cx43 is an unlikely target to reverse BC dormancy because of its role as a hematopoietic regulator. We found N-cadherin (CDH2) and its associated pathways as potential drug targets. CDH2, highly expressed in CSCs, interacts intracellularly with Cx43, colocalizes with Cx43 in BC cells within BM biopsies of patients, and is required for Cx43-mediated gap junctional intercellular communication with BM niche cells. Notably, CDH2 and anti-apoptotic pathways maintained BC dormancy. We thereby propose these pathways as potential pharmacological targets to prevent dormancy and chemosensitize resistant CSCs.

Summary: Mutant KRAS and c-MYC are oncogenic drivers and rational therapeutic targets for the treatment of pancreatic cancer. Although tumor growth and homeostasis are largely dependent on these oncogenes, a few residual cancer cells are able to survive the ablation of mutant KRAS and c-MYC. By performing a genome-wide gene expression analysis of in vivo-derived bulk tumor cells and residual cancer cells lacking the expression of mutant KRAS or c-MYC, we have identified an increase in autocrine IGF1/AKT signaling as a common survival mechanism in dormant cancer cells. The pharmacological inhibition of IGF-1R reduces residual disease burden and cancer recurrence, suggesting that this molecular pathway is crucial for the survival of cancer cells in the absence of the primary oncogenic drivers. : Rajbhandari et al. demonstrate that an increase in autocrine IGF1 signaling mediates the survival of residual pancreatic cancer cells following the ablation of oncogenic drivers (mutant KRAS and c-MYC). They provide experimental evidence that inhibiting IGF-1R can eradicate minimal residual disease and reduce cancer recurrence in vivo. Keywords: pancreatic cancer, oncogenes, KRAS, c-MYC, cancer dormancy, mouse models, genetic engineering, IGF1 signaling, AKT

Breast cancers have a poorer prognosis if estrogen receptor expression was lost during recurrence. It is unclear whether this conversion is cell autonomous or whether it can be promoted by the microenvironment during cancer dormancy. We explored the ability of marrow-derived stromal cell lines to arrest co-cultured breast cancer cells and suppress estrogen receptor alpha (ER) expression during arrest, facilitating the emergence of estrogen-independent breast cancer clones.Cancer cell growth, ER protein, microRNA, and mRNA levels were measured in breast cancer cell lines exposed to conditioned medium from marrow stromal lines in the presence and absence of estrogen and of signaling pathway modulators.We demonstrate that paracrine signaling from the stromal cell line HS5 downregulated ER in T47D and MCF7 breast cancer cells. This occurred at the mRNA level and also through decreased ER protein stability. Additionally, conditioned medium (CM) from HS5 arrested the breast cancer cells in G0/G1 in part through interleukin-1 (IL1) and inhibited cancer cell growth despite the activation of proliferative pathways (Erk and AKT) by the CM. Similar findings were observed for CM from the hFOB 1.19 osteoblastic cell line but not from two other fibroblastic marrow lines, HS27A and KM101. HS5-CM inhibition of MCF7 proliferation could not be restored by exogenous ER, but was restored by the IL1-antagonist IL1RA. In the presence of IL1RA, HS5-CM activation of AKT and Erk enabled the outgrowth of breast cancer cells with suppressed ER that were fulvestrant-resistant and estrogen-independent.We conclude that marrow-derived stromal cells can destabilize estrogen receptor protein to convert the ER status of growth-arrested ER+ breast cancer cell lines. The balance between stromal pro- and anti-proliferative signals controlled the switch from a dormant phenotype to estrogen-independent cancer cell growth.

Triple-negative breast cancer (TNBC) is a molecular subtype of breast malignancy with a poor clinical prognosis. There is growing evidence that some chemotherapeutic agents induce an adaptive anti-tumor immune response. This reaction has been proposed to maintain the equilibrium phase of the immunoediting process and to control tumor growth by immunological cancer dormancy. We recently reported a model of immunological breast cancer dormancy based on the murine 4T1 TNBC model. Treatment of 4T1 cells in vitro with high-dose chemotherapy activated the type I interferon (type I IFN) signaling pathway, causing a switch from immunosuppressive to cytotoxic T lymphocyte-dependent immune response in vivo, resulting in sustained dormancy. Here, we developed a deterministic mathematical model based on the assumption that two cell subpopulations exist within the treated tumor: one population with high type I IFN signaling and immunogenicity and lower growth rate, the other population with low type I IFN signaling and immunogenicity and higher growth rate. The model reproduced cancer dormancy, elimination, and immune-escape in agreement with our previously reported experimental data. It predicted that the injection of dormant tumor cells with active type I IFN signaling results in complete growth control of the aggressive parental cancer cells injected at a later time point, but also of an already established aggressive tumor. Taken together, our results indicate that a dormant cell population can suppress the growth of an aggressive counterpart by eliciting a cytotoxic T lymphocyte-dependent immune response.

Cancer cell heterogeneity is a universal feature of human tumors and represents a significant barrier to the efficacy and duration of anticancer therapies, especially targeted therapeutics. Among the heterogeneous cancer cell populations is a subpopulation of relatively quiescent cancer cells, which are in the G0/G1 cell-cycle phase and refractory to anti-mitotic drugs that target proliferative cells. These slow-cycling cells (SCCs) preexist in untreated tumors and frequently become enriched in treatment-failed tumors, raising the possibility that these cells may mediate therapy resistance and tumor relapse. Here we review several general concepts on tumor cell heterogeneity, quiescence, and tumor dormancy. We discuss the potential relationship between SCCs and cancer stem cells (CSCs). We also present our current understanding of how SCCs and cancer dormancy might be regulated. Increasing knowledge of SCCs and tumor dormancy should lead to identification of novel molecular regulators and therapeutic targets of tumor relapse, residual diseases, and metastasis.

Mechanosensing is increasingly recognised as important for tumour progression. Tumours become stiff and the forces that normally balance in the healthy organism break down and become imbalanced, leading to increases in migration, invasion and metastatic dissemination. Here, we review recent advances in our understanding of how extracellular matrix properties, such as stiffness, viscoelasticity and architecture control cell behaviour. In addition, we discuss how the tumour microenvironment can be modelled in vitro, capturing these mechanical aspects, to better understand and develop therapies against tumour spread. We argue that by gaining a better understanding of the microenvironment and the mechanical forces that govern tumour dynamics, we can make advances in combatting cancer dormancy, recurrence and metastasis. Electronic supplementary material The online version of this article (10.1007/s12551-018-0466-8) contains supplementary material, which is available to authorized users.

Cancer dormancy is a period of cancer progression in which residual tumor cells exist, but clinically remain asymptomatic for a long time, as well as resistant to conventional chemo- and radiotherapies. Cellular phenotype plasticity represents that cellular phenotype could convert between epithelial cells and cells with mesenchymal traits. Recently, this process has been shown to closely associate with tumor cell proliferation, cancer dormancy and metastasis. In this review, we have described different scenarios of how the transition from epithelial to mesenchymal morphology (EMT) and backwards (MET) are connected with the initiation of dormancy and reactivation of proliferation. These processes are fundamental for cancer cells to invade tissues and metastasize. Recognizing the mechanisms underlying the cellular phenotype plasticity as well as dormancy and targeting them is likely to increase the efficiency of traditional tumor treatment inhibiting tumor metastasis.

Background While hypoxia has been well-studied in various tumor microenvironments, its role in cancer cell dormancy is poorly understood, in part due to a lack of well-established in vitro and in vivo models. Hypoxic conditions under conventional hypoxia chambers are relatively unstable and cannot be maintained during characterization outside the chamber since normoxic response is quickly established. To address this challenge, we report a robust in vitro cancer dormancy model under a hypoxia-mimicking microenvironment using cobalt chloride (CoCl2), a hypoxia-mimetic agent, which stabilizes hypoxia inducible factor 1-alpha (HIF1α), a major regulator of hypoxia signaling. Methods We compared cellular responses to CoCl2 and true hypoxia (0.1% O2) in different breast cancer cell lines (MCF-7 and MDA-MB-231) to investigate whether hypoxic regulation of breast cancer dormancy could be mimicked by CoCl2. To this end, expression levels of hypoxia markers HIF1α and GLUT1 and proliferation marker Ki67, cell growth, cell cycle distribution, and protein and gene expression were evaluated under both CoCl2 and true hypoxia. To further validate our platform, the ovarian cancer cell line OVCAR-3 was also tested. Results Our results demonstrate that CoCl2 can mimic hypoxic regulation of cancer dormancy in MCF-7 and MDA-MB-231 breast cancer cell lines, recapitulating the differential responses of these cell lines to true hypoxia in 2D and 3D. Moreover, distinct gene expression profiles in MCF-7 and MDA-MB-231 cells under CoCl2 treatment suggest that key cell cycle components are differentially regulated by the same hypoxic stress. In addition, the induction of dormancy in MCF-7 cells under CoCl2 treatment is HIF1α-dependent, as evidenced by the inability of HIF1α-suppressed MCF-7 cells to exhibit dormant behavior upon CoCl2 treatment. Furthermore, CoCl2 also induces and stably maintains dormancy in OVCAR-3 ovarian cancer cells. Conclusions These results demonstrate that this CoCl2-based model could provide a widely applicable in vitro platform for understanding induction of cancer cell dormancy under hypoxic stress. Electronic supplementary material The online version of this article (10.1186/s13036-018-0106-7) contains supplementary material, which is available to authorized users.

International audience; Objective: Modeling and analysis of cell population dynamics enhance our understanding of cancer. Here we introduce and explore a new model that may apply to many tissues. Analyses: An age-structured model describing coexistence between mutated and ordinary stem cells is developed and explored. The model is transformed into a nonlin-ear time-delay system governing the dynamics of healthy cells, coupled to a nonlinear differential-difference system describing dynamics of unhealthy cells. Its main features are highlighted and an advanced stability analysis of several steady states is performed, through specific Lyapunov-like functionals for descriptor-type systems. Results: We propose a biologically based model endowed with rich dynamics. It incorporates a new parameter representing immunoediting processes, including the case where proliferation of cancer cells is locally kept under check by the immune cells. It also considers the overproliferation of cancer stem cells, modeled as a subpopulation of mutated cells that is constantly active in cell division. The analysis that we perform here reveals the conditions of existence of several steady states, including the case of cancer dormancy, in the coupled model of interest. Our study suggests that cancer dormancy may result from a plastic sensitivity of mutated cells to their shared environment, different from that-fixed-of healthy cells, and this is related to an action (or lack of action) of the immune system. Next, the stability analysis that we perform is essentially oriented towards the determination of sufficient conditions, depending on all the model parameters, that ensure either a regionally (i.e., locally) stable dormancy steady state or eradication of unhealthy cells. Finally, we discuss some biological interpretations, with regards to our findings, in light of current and emerging therapeutics. These final insights are particularly formulated in the paradigmatic case of hematopoiesis and acute leukemia, which is one of the best known malignancies for which it is always hard, in presence of a clinical and histological remission, to decide between cure and dormancy of a tumoral clone. 4 E. Fridman is with the Department of Electrical Engineering and Systems at the School of Electrical Engineering, Tel-Aviv, Israel. emilia@eng.tau.ac.il 5 P. Hirsch and F. Delhommeau are with Sorbonne Université, GRC n7, Groupe de Recherche Clinique sur les Myéloproliferations Aiguës et Chroniques, AP-HP, Hôpital Saint-Antoine, 2010 MSC: 93C23, 93C10, 93A30, 93D05, 92B05, 92C50, 80A30, 37L15, 39A30, 39A60. Highlights (to appear before the abstract in JTB template) • Modeling the cell cycle and population cell dynamics taking into account: coexistence between normal and mutated stem cells, overproliferation of cancer stem cells and sensitivity to the immune system. • The study of existence of different steady states, including: unhealthy cells eradication 5 and cancer cells dormancy (i.e. control in dormancy of abnormal cells). • Construction of different types of suitable strict Lyapunov-like functionals for nonlinear delay differential-difference systems. • Deriving stability conditions of steady states in different biological situations: a particular focus on the scenario of cancer dormancy. 10 • Numerical simulations, biological discussions and some therapeutic insights in the

Background: The discovery of mutations in epidermal growth factor receptor (EGFR) has dramatically changed the treatment of patients with non-small-cell lung cancer (NSCLC), the leading cause of cancer deaths worldwide. EGFR-targeted therapies show considerable promise, but drug resistance has become a substantial issue. Methods: We reviewed the literature to provide an overview of the drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. Results: The mechanisms causing primary, acquired and persistent drug resistance to TKIs vary. Researchers and clinicians, who have used study findings to develop more effective therapeutic approaches, have found that the sequential use of single agents presents a formidable challenge, suggesting that multidrug combinations must be considered. Conclusions: In the era of precision medicine, oncologists should promptly obtain an accurate diagnosis of drug resistance in each patient to be able to design the most relevant combination therapy to overcome patient-specific drug resistance.

Disease relapse in cancer patients many years after clinical remission, often referred to as cancer dormancy, is well documented but remains an incompletely understood phenomenon on the biologic level. Recent reviews have summarized potential models that can explain this phenomenon, including angiogenic, immunologic, and cellular dormancy. We focus on mechanisms of cellular dormancy as newer biologic insights have enabled better understanding of this process. We provide a historical context, synthesize current advances in the field, and propose a mechanistic framework that treats cancer cell dormancy as a dynamic cell state conferring a fitness advantage to an evolving malignancy under stress. Cellular dormancy appears to be an active process that can be toggled through a variety of signaling mechanisms that ultimately downregulate the RAS/MAPK and PI(3)K/AKT pathways, an ability that is preserved even in cancers that constitutively depend on these pathways for their growth and survival. Just as unbridled proliferation is a key hallmark of cancer, the ability of cancer cells to become quiescent may be critical to evolving malignancies, with implications for understanding cancer initiation, progression, and treatment resistance. Cancer Res; 75(23); 5014–22. ©2015 AACR.

The significant contribution of host immunity in early tumorigenesis has been recently recognized as a result of our better understanding of the molecular pathways regulating tumor cell biology and tumor-lymphocyte interactions. Emerging evidence suggests that disseminated dormant tumor cells derived from primary tumors before or after immune surveillance, are responsible for subsequent metastases. Recent trends from the field of onco-immunology suggest that efficiently stimulating endogenous anticancer immunity is a prerequisite for the successful outcome of conventional cancer therapies. Harnessing the immune system to achieve clinical efficacy is realistic in the context of conventional therapies resulting in immunogenic cell death and/or immunostimulatory side effects. Targeted therapies designed to target oncogenic pathways in tumor cells can also positively regulate the endogenous immune response and tumor microenvironment. Identification of T cell inhibitory signals has prompted the development of immune checkpoint inhibitors, which specifically hinder immune effector inhibition, reinvigorating and potentially expanding the preexisting anticancer immune response. This anticancer immunity can be amplified in the setting of immunotherapies, mostly in the form of vaccines, which boost naturally occurring T cell clones specifically recognizing tumor antigens. Thus, a promising anticancer therapy will aim to activate patients’ naturally occurring anticancer immunity either to eliminate residual tumor cells or to prolong dormancy in disseminated tumor cells. Such an endogenous anticancer immunity plays a significant role for controlling the balance between dormant tumor cells and tumor escape, and restraining metastases. In this review, we mean to suggest that anticancer therapies aiming to stimulate the endogenous antitumor responses provide the concept of the therapeutic management of cancer.

R.E. acknowledges support from an Engineering and Physical Sciences Research Council (UK) First Grant number EP/K033689/1 The main priority when designing cancer immuno-therapies has been to seek viable biological mechanisms that lead to permanent cancer eradication or cancer control. Understanding the delicate balance between the role of effector and memory cells on eliminating cancer cells remains an elusive problem in immunology. Here we make an initial investigation into this problem with the help of a mathematical model for oncolytic virotherapy; although the model can in fact be made general enough to be applied also to other immunological problems. Our results show that long-term cancer control is associated with a large number of persistent effector cells (irrespective of the initial peak in effector cell numbers). However, this large number of persistent effector cells is sustained by a relatively large number of memory cells. Moreover, we show that cancer control from a dormant state cannot be predicted by the size of the memory population. Postprint

The goal of this paper is to analyze a model of cancer-immune system interactions from [16], and to show how the introduction of control in this model can dramatically improve the hypothetical patient response and in effect prevent the cancer from growing. We examine all the equilibrium points of the model and classify them according to their stability properties. We identify an equilibrium point corresponding to a survivable amount of cancer cells which are exactly balanced by the immune response. This situation corresponds to cancer dormancy. By using Lyapunov stability theory we estimate the region of attraction of this equilibrium and propose two control laws which are able to stabilize the system effectively, improving the results of [16]. Ultimately, the analysis presented in this paper reveals that a slower, continuous introduction of antibodies over a short time scale, as opposed to mere inoculation, may lead to more efficient and safer treatments.

Cancer stem cells (CSCs) have been implicated as the seeds of treatment resistance and metastasis, which are the most deadly features of a neoplasm. However, an unequivocal definition of the CSC phenotype is still missing. A common feature of normal and aberrant stem cells is their ability to enter a prolonged dormant state. Cancer dormancy is a key mechanism for treatment resistance and metastasis. Here we propose a unified definition of dormancy-competent CSCs (DCCs) as the neoplastic subpopulation that can plastically alternate periods of dormancy and rapid growth. Irreversible DNA mutations can hardly account for this versatile behavior, and based on emerging evidence we propose that cancer dormancy is a nongenetic disease driven by the flexible nature of the epigenetic/noncoding interactome.

Minimal residual disease (MRD) is a major hurdle in the eradication of malignant tumors. Despite the high sensitivity of various cancers to treatment, some residual cancer cells persist and lead to tumor recurrence and treatment failure. Obvious reasons for residual disease include mechanisms of secondary therapy resistance, such as the presence of mutant cells that are insensitive to the drugs, or the presence of cells that become drug resistant due to activation of survival pathways. In addition to such unambiguous resistance modalities, several patients with relapsing tumors do not show refractory disease and respond again when the initial therapy is repeated. These cases cannot be explained by the selection of mutant tumor cells, and the precise mechanisms underlying this clinical drug resistance are ill-defined. In the current review, we put special emphasis on cell-intrinsic and -extrinsic mechanisms that may explain mechanisms of MRD that are independent of secondary therapy resistance. In particular, we show that studying genetically engineered mouse models (GEMMs), which highly resemble the disease in humans, provides a complementary approach to understand MRD. In these animal models, specific mechanisms of secondary resistance can be excluded by targeted genetic modifications. This allows a clear distinction between the selection of cells with stable secondary resistance and mechanisms that result in the survival of residual cells but do not provoke secondary drug resistance. Mechanisms that may explain the latter feature include special biochemical defense properties of cancer stem cells, metabolic peculiarities such as the dependence on autophagy, drug-tolerant persisting cells, intratumoral heterogeneity, secreted factors from the microenvironment, tumor vascularization patterns and immunosurveillance-related factors. We propose in the current review that a common feature of these various mechanisms is cancer cell dormancy. Therefore, dormant cancer cells appear to be an important target in the attempt to eradicate residual cancer cells, and eventually cure patients who repeatedly respond to anticancer therapy but lack complete tumor eradication.

Multiple myeloma (MM) is characterized by accumulation of clonal plasma cells (PCs) predominantly in the bone marrow but tumor cells appear in the circulation in significant numbers as the disease progress. The occurrence of circulating multiple myeloma cells raises question concerning interactions between these cells and stroma of peripheral organs specifically under certain pathophysiological conditions, e.g., inflammation. Therefore, in the present study we exposed three human multiple myeloma cell lines to sterile inflammation produced in a culture dish by clusters of cell-cell contact-activated dermal fibroblasts. We now observed that myeloma cells responded differently to this particular type of stromal cell activation, nemosis. Two cell lines U-266 and LP-1 were minimally affected by the proinflammatory signalling, while the third cell line RPMI 8226 responded with growth arrest and altered expression of three phenotypic markers CD38, CD45, and CD138, indicating dedifferentiation shift of these cells to less mature PC-like phenotype. In a preliminary study we identified a subclone of cells having similar phenotype in 14 out of 23 analysed specimens of MM patients. This set of data indicates that the observed phenomenon might be clinically relevant. Our results emphasize the potential role of activated stromal fibroblasts and subsequent inflammation in altering phenotype of PCs and directing myeloma progression towards dormancy. Given the significant implication of dormant myeloma cells that might serve as a major cellular basis for the relapse, understanding their unique biology and precise elucidation of the underlying molecular mechanisms for the maintenance of quiescence is important. Therefore, we consider this study as a particular contribution to development of experimental model for in vitro studies of cancer dormancy.