Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer

Han, Jincheng; Xu, Jiaqian; Liu, Yonghong; Liang, Shaoheng; LaBella, Kyle A.; Chakravarti, Deepavali; Spring, Denise J.; Xia, Yan; DePinho, Ronald A.

doi:10.1101/gad.351037.123

Cited by 7 publications

(3 citation statements)

References 29 publications

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“…Remarkably, EGFR-activated myCAFs promote PDAC metastasis [ 56 ]. On the other hand, the CAFs-derived NRG1 (SE = 3.6) activation of cancer cell ERBB2 and ERBB3 receptor tyrosine kinases as a paracrine mechanism supports mutant KRAS-independent growth ( Figure 4 ) [ 57 ]. AREG and NRG1 expressions in cancer stroma were not closely associated with CAFGs ( LRRC15 , R = 0.04 and 0.03, respectively) at all, suggesting that EGFR ligands-expressed CAFs may be unique subpopulations among CAFs.…”

Section: Semi-cafgs In Pdac and Novel Therapeutic Potentialmentioning

confidence: 99%

CAFs-Associated Genes (CAFGs) in Pancreatic Ductal Adenocarcinoma (PDAC) and Novel Therapeutic Strategy

Yamashita,

Kumamoto

2024

IJMS

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Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive cancer with striking fibrosis, and its mortality rate is ranked second across human cancers. Cancer-associated fibroblasts (CAFs) play a critical role in PDAC progression, and we reviewed the molecular understanding of PDAC CAFs and novel therapeutic potential at present. CAFs-associated genes (CAFGs) were tentatively classified into three categories by stroma specificity representing stroma/epithelia expression ratios (SE ratios). The recent classification using single cell transcriptome technology clarified that CAFs were composed of myofibroblasts (myCAFs), inflammatory CAFs (iCAFs), and other minor ones (e.g., POSTN-CAFs and antigen presenting CAFs, apCAFs). LRRC15 is a myCAFs marker, and myCAFs depletion by diphtheria toxin induces the rapid accumulation of cytotoxic T lymphocytes (CTLs) and therefore augment PDL1 antibody treatments. This finding proposes that myCAFs may be a critical regulator of tumor immunity in terms of PDAC progression. myCAFs are located in CAFs adjacent to tumor cells, while iCAFs marked by PDPN and/or COL14A1 are distant from tumor cells, where hypoxic and acidic environments being located in iCAFs putatively due to poor blood supply is consistent with HIF1A and GPR68 expressions. iCAFs may be shared with SASP (secretion-associated phenotypes) in senescent CAFs. myCAFs are classically characterized by CAFGs induced by TGFB1, while chemoresistant CAFs with SASP may dependent on IL6 expression and accompanied by STAT3 activation. Recently, it was found that the unique metabolism of CAFs can be targeted to prevent PDAC progression, where PDAC cells utilize glucose, whereas CAFs in turn utilize lactate, which may be epigenetically regulated, mediated by its target genes including CXCR4. In summary, CAFs have unique molecular characteristics, which have been rigorously clarified as novel therapeutic targets of PDAC progression.

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Section: Semi-cafgs In Pdac and Novel Therapeutic Potentialmentioning

confidence: 99%

CAFs-Associated Genes (CAFGs) in Pancreatic Ductal Adenocarcinoma (PDAC) and Novel Therapeutic Strategy

Yamashita,

Kumamoto

2024

IJMS

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“…Researchers have shown that TGF-β in myCAFs can activate EGFR/ERBB2 signaling via an amphiregulin-mediated autocrine process, providing new theoretical support for EGFR-targeted therapy. Moreover, the only ligand involved in the ERBB2 pathway is neuregulin-1 (NRG1), and the expression of NRG1 on CAFs was shown to result in resistance to KRAS inhibitors [ 110 ]. Researchers also reported the upregulation of ERBB2 and ERBB3 in PDAC samples after KRAS inhibition, and most patients with recurrent tumors were examined for novel KRAS or downstream RTK/PI3K/MAPK pathway mutations.…”

Section: Decoding the Stromal Component In The Tme: Restricting Tumor...mentioning

confidence: 99%

“…However, resistance to KRAS inhibitors is also common. The effects of targeting KRAS signaling or downstream MEK signaling were temporary, but most tumors recurred soon after [ 110 ]. CAFs were shown to play a key role in promoting resistance to KRAS inhibitors.…”

Section: Decoding the Stromal Component In The Tme: Restricting Tumor...mentioning

confidence: 99%

Unbiasedly decoding the tumor microenvironment with single-cell multiomics analysis in pancreatic cancer

Fu,

Tao,

Liu

et al. 2024

Mol Cancer

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis and limited therapeutic options. Research on the tumor microenvironment (TME) of PDAC has propelled the development of immunotherapeutic and targeted therapeutic strategies with a promising future. The emergence of single-cell sequencing and mass spectrometry technologies, coupled with spatial omics, has collectively revealed the heterogeneity of the TME from a multiomics perspective, outlined the development trajectories of cell lineages, and revealed important functions of previously underrated myeloid cells and tumor stroma cells. Concurrently, these findings necessitated more refined annotations of biological functions at the cell cluster or single-cell level. Precise identification of all cell clusters is urgently needed to determine whether they have been investigated adequately and to identify target cell clusters with antitumor potential, design compatible treatment strategies, and determine treatment resistance. Here, we summarize recent research on the PDAC TME at the single-cell multiomics level, with an unbiased focus on the functions and potential classification bases of every cellular component within the TME, and look forward to the prospects of integrating single-cell multiomics data and retrospectively reusing bulk sequencing data, hoping to provide new insights into the PDAC TME.

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