Single Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression

Bernard, Vincent; Semaan, Alexander; Huang, Jonathan; Lucas, F. Anthony San; Mulu, Feven C.; Stephens, Bret M.; Guerrero, Paola A.; Huang, Yanqing; Zhao, Jun; Kamyabi, Nabiollah; Sen, Subrata; Scheet, Paul; Taniguchi, Cullen M.; Kim, Michael P.; Tzeng, Ching‐Wei D.; Katz, Matthew H.G.; Singhi, Aatur D.; Maitra, Anirban; Alvarez, Hector A.

doi:10.1101/306134

Cited by 26 publications

(27 citation statements)

References 53 publications

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“…The function of Ly-6C remains widely unknown, yet, it is mainly associated with the immune system, and inflammatory events (63–65). We identified Ly-6C as characteristic marker for CAFs, which is in line with current literature (66–68). Ly-6C has been introduced as cell surface marker characteristic for a subpopulation of activated (cancer-associated) fibroblasts, termed inflammatory CAFs [iCAFs; (66–68)].…”

Section: Discussionsupporting

confidence: 90%

“…We identified Ly-6C as characteristic marker for CAFs, which is in line with current literature (66–68). Ly-6C has been introduced as cell surface marker characteristic for a subpopulation of activated (cancer-associated) fibroblasts, termed inflammatory CAFs [iCAFs; (66–68)]. However, our data suggested Ly-6C to be a general fibroblast marker upregulated upon activation or proliferation and generally overexpressed in CAFs.…”

Section: Discussionsupporting

confidence: 90%

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CD49b, CD87, and CD95 Are Markers for Activated Cancer-Associated Fibroblasts Whereas CD39 Marks Quiescent Normal Fibroblasts in Murine Tumor Models

et al. 2019

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Fibroblasts are thought to be key players in the tumor microenvironment. Means to identify and isolate fibroblasts as well as an understanding of their cancer-specific features are essential to dissect their role in tumor biology. To date, the identification of cancer-associated fibroblasts is widely based on generic markers for activated fibroblasts in combination with their origin in tumor tissue. This study was focused on a deep characterization of the cell surface marker profile of cancer-associated fibroblasts in widely used mouse tumor models and defining aberrant expression profiles by comparing them to their healthy counterparts. We established a generic workflow to isolate healthy and cancer-associated fibroblasts from solid tissues, thereby reducing bias, and background noise introduced by non-target cells. We identified CD87, CD44, CD49b, CD95, and Ly-6C as cancer-associated fibroblast cell surface markers, while CD39 was identified to mark normal fibroblasts from healthy tissues. In addition, we found a functional association of most cancer-related fibroblast markers to proliferation and a systemic upregulation of CD87, and CD49b in tumor-bearing mice, even in non-affected tissues. These novel markers will facilitate the characterization of fibroblasts and shed further light in their functions and implication in cancer progression.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 90%

CD49b, CD87, and CD95 Are Markers for Activated Cancer-Associated Fibroblasts Whereas CD39 Marks Quiescent Normal Fibroblasts in Murine Tumor Models

et al. 2019

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“…Furthermore, we found that CAFs are a major source of TGFb-induced IL-6 expression. Several recent studies including ours demonstrate the existence of fibroblast heterogeneity within PDA (Ohlund et al, 2017;Bernard et al, 2019;Elyada et al, 2019;Hosein et al, 2019). Two major populations of CAFs have been identified, one is characterized by an inflammatory feature, while the other has been known as myofibroblast.…”

Section: Discussionmentioning

confidence: 68%

“…Recently, several studies, including ours, suggest the existence of two different subtypes of CAFs in PDA (Ohlund et al, 2017;Bernard et al, 2019;Elyada et al, 2019;Hosein et al, 2019). Of the two CAF populations, one appears to be inflammatory, characterized by PDGFRa expression and the secretion of a variety of inflammatory chemokines.…”

mentioning

confidence: 70%

Targeting TGF βR2‐mutant tumors exposes vulnerabilities to stromal TGF β blockade in pancreatic cancer

et al. 2019

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TGFβ is important during pancreatic ductal adenocarcinoma (PDA) progression. Canonical TGFβ signaling suppresses epithelial pancreatic cancer cell proliferation; as a result, inhibiting TGFβ has not been successful in PDA. In contrast, we demonstrate that inhibition of stromal TGFβR2 reduces IL‐6 production from cancer‐associated fibroblasts, resulting in a reduction of STAT3 activation in tumor cells and reversion of the immunosuppressive landscape. Up to 7% of human PDA have tumor cell‐specific deficiency in canonical TGFβ signaling via loss of TGFβR2. We demonstrate that in PDA that harbors epithelial loss of TGFβR2, inhibition of TGFβ signaling is selective for stromal cells and results in a therapeutic benefit. Our study highlights the potential benefit of TGFβ blockade in PDA and the importance of stratifying PDA patients who might benefit from such therapy.

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“…Myeloid cell populations are highly heterogenous (30,31). While many myeloid cell populations can stimulate immune evasion via a wide range of immunosuppressive mechanisms, some myeloid cells have anti-tumor properties (32).…”

Section: Discussionmentioning

confidence: 99%

Immune Selection Pressure Contributes to Pancreatic Cancer Immune Evasion

Ajina

Zuo

Wang

et al. 2020

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Pancreatic tumors are minimally infiltrated by T cells and are largely refractory to immunotherapy. Accordingly, the role of T cell immunity in pancreatic cancer has been somewhat overlooked. Here, we hypothesized that immune evasion in pancreatic cancer is induced in response to T cell-based immune selection pressure, and that understanding how pancreatic tumors respond to immune attack may facilitate the development of more effective therapeutic strategies. We now provide the first evidence that T cell-dependent host immune responses induce a PDAC-derived myeloid mimicry phenomenon and stimulate immune evasion. mT3-2D cells derived from a Kras +/LSL-G12D ; Trp53 +/LSL-R172H ; Pdx1-Cre (KPC) mouse model of pancreatic cancer were grown in immunocompetent and immunodeficient C57BL/6 mice, and analyzed to determine the impacts of adaptive immunity specifically on malignant epithelial cells as well as on whole tumors. We found that immune selection pressure, via signal transducer and activator of transcription 1 (STAT1), stimulates malignant epithelial pancreatic cells to induce the expression of genes typically expressed by myeloid cells and alters intratumoral immunosuppressive myeloid cell profiles. Targeting the Janus Kinase (JAK)/STAT signaling pathway using the FDA approved drug, ruxolitinib, overcomes these tumor-protective responses and improves anti-PD1 antibody therapeutic efficacy. These findings provide future directions for treatments that specifically disable this mechanism of resistance in PDAC.

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Single Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression

Cited by 26 publications

References 53 publications

CD49b, CD87, and CD95 Are Markers for Activated Cancer-Associated Fibroblasts Whereas CD39 Marks Quiescent Normal Fibroblasts in Murine Tumor Models

CD49b, CD87, and CD95 Are Markers for Activated Cancer-Associated Fibroblasts Whereas CD39 Marks Quiescent Normal Fibroblasts in Murine Tumor Models

Targeting TGF βR2‐mutant tumors exposes vulnerabilities to stromal TGF β blockade in pancreatic cancer

Immune Selection Pressure Contributes to Pancreatic Cancer Immune Evasion

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