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For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as cancer therapeutics. Based on collective experience from the consortium groups, we provide insight regarding PDMCs established both in vitro and in vivo, with a focus on practical matters related to developing and maintaining key cancer models through a series of vignettes. Although every model has the potential to offer valuable insights, the choice of the right model should be guided by the research question. However, recognizing the inherent constraints in each model is crucial. Our objective here is to delineate the strengths and limitations of each model as established by individual vignettes. Further advances in PDMCs and the development of novel model systems will enable us to better understand human biology and improve the study of human pathology in the lab.

cMYC (MYC) is a potent oncoprotein that is subject to post-translational modifications that affect its stability and activity. Here, we show that Serine 62 phosphorylation, which increases MYC stability and oncogenic activity, is elevated while Threonine 58 phosphorylation, which targets MYC for degradation, is decreased in squamous cell carcinoma (SCC). The oncogenic role of MYC in the development of SCC is unclear since studies have shown in normal skin that wild-type MYC overexpression can drive loss of stem cells and epidermal differentiation. To investigate whether and how altered MYC phosphorylation might affect SCC development, progression, and metastasis, we generated mice with inducible expression of MYCWT or MYCT58A in the basal layer of the skin epidermis. In the T58A mutant, MYC is stabilized with constitutive S62 phosphorylation. When challenged with DMBA/TPA-mediated carcinogenesis, MYCT58A mice had accelerated development of papillomas, increased conversion to malignant lesions, and increased metastasis as compared to MYCWT mice. In addition, MYCT58A-driven SCC displayed stem cell gene expression not observed with MYCWT, including increased expression of Lgr6, Sox2, and CD34. In support of MYCT58A enhancing stem cell phenotypes, its expression was associated with an increased number of BrdU long-term label-retaining cells, increased CD34 expression in hair follicles, and increased colony formation from neonatal keratinocytes. Together, these results indicate that altering MYC phosphorylation changes its oncogenic activity-instead of diminishing establishment and/or maintenance of epidermal stem cell populations like wild-type MYC, pS62-MYC enhances these populations and, under carcinogenic conditions, pS62-MYC expression results in aggressive tumor phenotypes.

[This corrects the article DOI: 10.1371/journal.pcbi.1006840.].

Drug resistance in breast cancer cell populations has been shown to arise through phenotypic transition of cancer cells to a drug-tolerant state, for example through epithelial-to-mesenchymal transition or transition to a cancer stem cell state. However, many breast tumors are a heterogeneous mixture of cell types with numerous epigenetic states in addition to stem-like and mesenchymal phenotypes, and the dynamic behavior of this heterogeneous mixture in response to drug treatment is not well-understood. Recently, we showed that plasticity between differentiation states, as identified with intracellular markers such as cytokeratins, is linked to resistance to specific targeted therapeutics. Understanding the dynamics of differentiation-state transitions in this context could facilitate the development of more effective treatments for cancers that exhibit phenotypic heterogeneity and plasticity. In this work, we develop computational models of a drug-treated, phenotypically heterogeneous triple-negative breast cancer (TNBC) cell line to elucidate the feasibility of differentiation-state transition as a mechanism for therapeutic escape in this tumor subtype. Specifically, we use modeling to predict the changes in differentiation-state transitions that underlie specific therapy-induced changes in differentiation-state marker expression that we recently observed in the HCC1143 cell line. We report several statistically significant therapy-induced changes in transition rates between basal, luminal, mesenchymal, and non-basal/non-luminal/non-mesenchymal differentiation states in HCC1143 cell populations. Moreover, we validate model predictions on cell division and cell death empirically, and we test our models on an independent data set. Overall, we demonstrate that changes in differentiation-state transition rates induced by targeted therapy can provoke distinct differentiation-state aggregations of drug-resistant cells, which may be fundamental to the design of improved therapeutic regimens for cancers with phenotypic heterogeneity.

Intratumoral heterogeneity in cancers arises from genomic instability and epigenomic plasticity and is associated with resistance to cytotoxic and targeted therapies. We show here that cell-state heterogeneity, defined by differentiation-state marker expression, is high in triple-negative and basal-like breast cancer subtypes, and that drug tolerant persister (DTP) cell populations with altered marker expression emerge during treatment with a wide range of pathway-targeted therapeutic compounds. We show that MEK and PI3K/mTOR inhibitor-driven DTP states arise through distinct cell-state transitions rather than by Darwinian selection of preexisting subpopulations, and that these transitions involve dynamic remodeling of open chromatin architecture. Increased activity of many chromatin modifier enzymes, including BRD4, is observed in DTP cells. Co-treatment with the PI3K/mTOR inhibitor BEZ235 and the BET inhibitor JQ1 prevents changes to the open chromatin architecture, inhibits the acquisition of a DTP state, and results in robust cell death in vitro and xenograft regression in vivo.

We hypothesized that people at the borderline of being labeled as "prediabetic" based on A1c blood test results, who initially face equivalent risks of developing diabetes but who are labeled differently, would be more likely to develop diabetes when labeled as "prediabetic" as a result of the label. Study 1 served to establish the psychological effect of the prediabetes label: we surveyed 260 participants on Amazon Mechanical Turk to test whether risk perception significantly increased when comparing A1c test results that differed by 0.1% and led to different diagnostic labels (5.6 and 5.7%) but did not significantly increase when comparing those that differed by 0.1% but received the same label (5.5%/5.6 and 5.7%/5.8%). Study 2 explored whether labels are associated with different rates of developing diabetes when the initial difference in A1c results suggests equivalent risk. Using data from 8,096 patients, we compared patients whose initial A1c results differed by 0.1% and found those who received results labeled as prediabetic (A1c of 5.7%) were significantly more likely to develop diabetes than patients whose initial results were labeled as normal (5.6%). In contrast, patients whose initial results differed by 0.1% but who received the same "normal" label (5.5 and 5.6%) were equally likely to develop diabetes. These preliminary results suggest that diagnostic labels may become self-fulfilling, especially when the underlying pathology of patients receiving different labels does not meaningfully differ. [ABSTRACT FROM AUTHOR]

The c-MYC (MYC) oncoprotein is often overexpressed in human breast cancer; however, its role in driving disease phenotypes is poorly understood. Here, we investigate the role of MYC in [HER2.sup.+] disease, examining the relationship between HER2 expression and MYC phosphorylation in [HER2.sup.+] patient tumors and characterizing the functional effects of deregulating MYC expression in the murine NeuNT model of amplified-HER2 breast cancer. Deregulated MYC alone was not tumorigenic, but coexpression with NeuNT resulted in increased MYC Ser62 phosphorylation and accelerated tumorigenesis. The resulting tumors were metastatic and associated with decreased survival compared with NeuNT alone. MYC; NeuNT tumors had increased intertumoral heterogeneity including a subtype of tumors not observed in NeuNT tumors, which showed distinct metaplastic histology and worse survival. The distinct subtypes of MYC; NeuNT tumors match existing subtypes of amplified-HER2, estrogen receptor-negative human tumors by molecular expression, identifying the preclinical utility of this murine model to interrogate subtype-specific differences in amplified-HER2 breast cancer. We show that these subtypes have differential sensitivity to clinical HER2/EGFR-targeted therapeutics, but small-molecule activators of PP2A, the phosphatase that regulates MYC Ser62 phosphorylation, circumvents these subtype-specific differences and ubiquitously suppresses tumor growth, demonstrating the therapeutic utility of this approach in targeting deregulated MYC breast cancers., Introduction Amplified-HER2 breast cancer is an aggressive disease that until recently had the worst overall survival prognosis among breast cancer subtypes (1, 2). The clinical implementation of HER2-targeted therapies, including [...]

Results reveal that the deamidation of two asparagines in the Bcl-x(sub)L gene renders tumor cells susceptible to apoptosis by inhibiting the gene's ability to block the proapoptotic activity of BH3 domain-only proteins leading to the DNA damage-induced apoptosis.