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Surgery remains the only curative treatment of pancreatic neuroendocrine neoplasms (pNEN). Here, we report the outcome after surgery for non-functional pNEN at a European Neuroendocrine Tumor Society (ENETS) center in Germany between 2000 and 2019, cases were analyzed for surgical (Clavien–Dindo classification, CDc) and oncological outcomes. Forty-nine patients (tumor grading G1 n = 25, G2 n = 22, G3 n = 2), with a median age of 56 years, were included. Severe complications (CDc ≥ grade 3b) occurred in 11 patients (22.4%) and type B/C pancreatic fistulas (POPFs) occurred in 5 patients (10.2%), in-hospital mortality was 2% (n = 1). Six of seven patients with tumor recurrence (14.3%) had G2 tumors in the pancreatic body/tail. The median survival was 5.7 years (68 months, [1–228 months]). Neither the occurrence (p = 0.683) nor the severity of complications had an influence on the relapse behavior (p = 0.086). This also applied for a POPF (≥B, p = 0.609). G2 pNEN patients (n = 22) with and without tumor recurrence had similar median tumor sizes (4 cm and 3.9 cm, respectively). Five of the six relapsed G2 patients (83.3%) had tumor-positive lymph nodes (N+), all G2 pNEN patients with recurrence had initially been treated with distal pancreatic resection. Pancreatic resections for pNEN are safe but associated with relevant postoperative morbidity. Future studies are needed to evaluate suitable resection strategies for G2 pNEN.

Pancreatic neuroendocrine neoplasms (pNENs) account for approximately 5% of all pancreatic tumors; thus, they constitute the second most common tumor type in the pancreas [...]

Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancer types with the quasi-mesenchymal (QM) subtype of PDAC having the worst prognosis. De-differentiation of the ductal tumor cells to a mesenchymal phenotype occurs as a result of epithelial–mesenchymal transition (EMT), a process associated with the acquisition of stem cell traits. While QM tumor cells are highly metastatic and drug-resistant, their increased plasticity opens a window of opportunity for trans-differentiation into non-malignant pancreatic cells. In this study we compared established PDAC-derived cell lines of either epithelial (E) or QM phenotype for their potential to be differentiated to pancreatic endocrine cells. We found that QM cells responded more strongly than E cells with transcriptional activation of a pancreatic progenitor or pancreatic β cell-specific program. Our results bear strong implications for a novel type of targeted therapy, namely EMT-based trans-differentiation of highly metastatic PDAC cells in vivo to non-malignant endocrine cells. Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and therapy-resistant cancer types which is largely due to tumor heterogeneity, cancer cell de-differentiation, and early metastatic spread. The major molecular subtypes of PDAC are designated classical/epithelial (E) and quasi-mesenchymal (QM) subtypes, with the latter having the worst prognosis. Epithelial–mesenchymal transition (EMT) and the reverse process, mesenchymal-epithelial transition (MET), are involved in regulating invasion/metastasis and stem cell generation in cancer cells but also early pancreatic endocrine differentiation or de-differentiation of adult pancreatic islet cells in vitro, suggesting that pancreatic ductal exocrine and endocrine cells share common EMT programs. Using a panel of PDAC-derived cell lines classified by epithelial/mesenchymal expression as either E or QM, we compared their trans-differentiation (TD) potential to endocrine progenitor or β cell-like cells since studies with human pancreatic cancer cells for possible future TD therapy in PDAC patients are not available so far. We observed that QM cell lines responded strongly to TD culture using as inducers 5′-aza-2′-deoxycytidine or growth factors/cytokines, while their E counterparts were refractory or showed only a weak response. Moreover, the gain of plasticity was associated with a decrease in proliferative and migratory activities and was directly related to epigenetic changes acquired during selection of a metastatic phenotype as revealed by TD experiments using the paired isogenic COLO 357-L3.6pl model. Our data indicate that a QM phenotype in PDAC coincides with increased plasticity and heightened trans-differentiation potential to activate a pancreatic β cell-specific transcriptional program. We strongly assume that this specific biological feature has potential to be exploited clinically in TD-based therapy to convert metastatic PDAC cells into less malignant or even benign cells.

Autocrine transforming growth factor (TGF)&beta, has been implicated in epithelial-mesenchymal transition (EMT) and invasion of several cancers including pancreatic ductal adenocarcinoma (PDAC) as well as triple-negative breast cancer (TNBC). However, the precise mechanism and the upstream inducers or downstream effectors of endogenous TGFB1 remain poorly characterized. In both cancer types, the small GTPase RAC1B inhibits cell motility induced by recombinant human TGF&beta, 1 via downregulation of the TGF&beta, type I receptor, ALK5, but whether RAC1B also impacts autocrine TGF&beta, signaling has not yet been studied. Intriguingly, RNA interference-mediated knockdown (RNAi-KD) or CRISPR/Cas-mediated knockout of RAC1B in TGF&beta, 1-secreting PDAC-derived Panc1 cells resulted in a dramatic decrease in secreted bioactive TGF&beta, 1 in the culture supernatants and TGFB1 mRNA expression, while the reverse was true for TNBC-derived MDA-MB-231 cells ectopically expressing RAC1B. Surprisingly, the antibody-mediated neutralization of secreted bioactive TGF&beta, or RNAi-KD of the endogenous TGFB1 gene, was associated with increased rather than decreased migratory activities of Panc1 and MDA-MB-231 cells, upregulation of the promigratory genes SNAI1, SNAI2 and RAC1, and downregulation of the invasion suppressor genes CDH1 (encoding E-cadherin) and SMAD3. Intriguingly, ectopic re-expression of SMAD3 was able to rescue Panc1 and MDA-MB-231 cells from the TGFB1 KD-induced rise in migratory activity. Together, these data suggest that RAC1B favors synthesis and secretion of autocrine TGF&beta, 1 which in a SMAD3-dependent manner blocks EMT-associated gene expression and cell motility.

Simple Summary Transforming growth factor (TGF) β signaling is intimately involved in nearly all aspects of tumor development and is known for its role as both a tumor suppressor in benign tissues and a tumor promoter in advanced cancers. This dual role is also reflected by cancer cell-produced TGFβ that eventually acts on the same cell(s) in an autocrine fashion. Recently, we observed that endogenous TGFB1 can inhibit rather than stimulate cell motility in cell lines with high autocrine TGFβ production. The unexpected anti-migratory role prompted us to evaluate how autocrine TGFβ1 impacts the cells’ migratory and proliferative responses to exogenous (recombinant human) TGFβ. Surprisingly, endogenous TGFB1 opposed the migratory and growth-inhibitory responses induced by exogenous TGFβ1 by driving a self-perpetuating feedforward loop involving MEK-ERK signaling. Our observation has implications for the use of TGFβ signaling inhibitors in cancer therapy. Abstract Autocrine transforming growth factor β (aTGFβ) has been implicated in the regulation of cell invasion and growth of several malignant cancers such as pancreatic ductal adenocarcinoma (PDAC) or triple-negative breast cancer (TNBC). Recently, we observed that endogenous TGFB1 can inhibit rather than stimulate cell motility in cell lines with high aTGFβ production and mutant KRAS, i.e., Panc1 (PDAC) and MDA-MB-231 (TNBC). The unexpected anti-migratory role prompted us to evaluate if aTGFβ1 may be able to antagonize the action of exogenous (recombinant human) TGFβ (rhTGFβ), a well-known promoter of cell motility and growth arrest in these cells. Surprisingly, RNA interference-mediated knockdown of the endogenous TGFB1 sensitized genes involved in EMT and cell motility (i.e., SNAI1) to up-regulation by rhTGFβ1, which was associated with a more pronounced migratory response following rhTGFβ1 treatment. Ectopic expression of TGFB1 decreased both basal and rhTGFβ1-induced migratory activities in MDA-MB-231 cells but had the opposite effect in Panc1 cells. Moreover, silencing TGFB1 reduced basal proliferation and enhanced growth inhibition by rhTGFβ1 and induction of cyclin-dependent kinase inhibitor, p21WAF1. Finally, we show that aTGFβ1 promotes MEK-ERK signaling and vice versa to form a self-perpetuating feedforward loop that is sensitive to SB431542, an inhibitor of the TGFβ type I receptor, ALK5. Together, these data suggest that in transformed cells an ALK5-MEK-ERK-aTGFβ1 pathway opposes the promigratory and growth-arresting function of rhTGFβ1. This observation has profound translational implications for TGFβ signaling in cancer.

Simple Summary Transforming growth factor β (TGFβ) promotes pancreatic ductal adenocarcinoma (PDAC) primarily through its non-canonical (non-Smad) signaling arms, including signaling by the small GTPase RAC1. The human RAC1 gene also encodes for another protein, designated RAC1B, but whether this isoform also interacts with TGFβ signaling has remained unknown. In a series of studies in PDAC-derived cells, we found that RAC1B also cross-talks with TGFβ signaling, but unlike RAC1 antagonizes TGFβ-induced responses, i.e., epithelial–mesenchymal transition, through multiple mechanisms. However, rather than being uniformly inhibitory, RAC1B selectively blocks tumor-promoting pathways, while concomitantly allowing tumor-suppressive pathways to proceed. In this review article, we discuss the specific interactions between RAC1B and TGFβ signaling, which occur at multiple levels and include various components of both the canonical Smad and non-Smad pathways. In addition to emerging as a novel tumor suppressor in PDAC, RAC1B turned out to be a useful tool to dissect TGFβ signaling. Abstract RAC1 and its alternatively spliced isoform, RAC1B, are members of the Rho family of GTPases. Both isoforms are involved in the regulation of actin cytoskeleton remodeling, cell motility, cell proliferation, and epithelial–mesenchymal transition (EMT). Compared to RAC1, RAC1B exhibits a number of distinctive features with respect to tissue distribution, downstream signaling and a role in disease conditions like inflammation and cancer. The subcellular locations and interaction partners of RAC1 and RAC1B vary depending on their activation state, which makes RAC1 and RAC1B ideal candidates to establish cross-talk with cancer-associated signaling pathways—for instance, interactions with signaling by transforming growth factor β (TGFβ), a known tumor promoter. Although RAC1 has been found to promote TGFβ-driven tumor progression, recent observations in pancreatic carcinoma cells surprisingly revealed that RAC1B confers anti-oncogenic properties, i.e., through inhibiting TGFβ-induced EMT. Since then, an unexpected array of mechanisms through which RAC1B cross-talks with TGFβ signaling has been demonstrated. However, rather than being uniformly inhibitory, RAC1B interacts with TGFβ signaling in a way that results in the selective blockade of tumor-promoting pathways, while concomitantly allowing tumor-suppressive pathways to proceed. In this review article, we are going to discuss the specific interactions between RAC1B and TGFβ signaling, which occur at multiple levels and include various components such as ligands, receptors, cytosolic mediators, transcription factors, and extracellular inhibitors of TGFβ ligands.