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Here, we show that autophagy is activated in the intestinal epithelium in murine and human colorectal cancer and that the conditional inactivation of Atg7 in intestinal epithelial cells inhibits the formation of pre-cancerous lesions in Apc(+/-) mice by enhancing anti-tumour responses. The antibody-mediated depletion of CD8(+) T cells showed that these cells are essential for the anti-tumoral responses mediated by the inhibition of autophagy. We show that Atg7 deficiency leads to intestinal dysbiosis and that the microbiota is required for anticancer responses. In addition, Atg7 deficiency resulted in a stress response accompanied by metabolic defects, AMPK activation and p53-mediated cell-cycle arrest in tumour cells but not in normal tissue. This study reveals that the inhibition of autophagy within the epithelium may prevent the development and progression of colorectal cancer in genetically predisposed patients.

Graphical AbstractHighlights d Loss of PKCl/i promotes basal and NEPC features in vivo d PKCl/i represses mTORC1 activation through LAMTOR2 phosphorylation d Loss of PKCl/i increases the SGOCP through mTORC1/ATF4 to fuel DNA methylation d The mTORC1/ATF4/PHGDH axis is a synthetic vulnerability of NEPC SUMMARY Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)l/i is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCl/i deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.

ObjectivesPolyploidy is a fascinating characteristic of liver parenchyma. Hepatocyte polyploidy depends on the DNA content of each nucleus (nuclear ploidy) and the number of nuclei per cell (cellular ploidy). Which role can be assigned to polyploidy during human hepatocellular carcinoma (HCC) development is still an open question. Here, we investigated whether a specific ploidy spectrum is associated with clinical and molecular features of HCC.DesignPloidy spectra were determined on surgically resected tissues from patients with HCC as well as healthy control tissues. To define ploidy profiles, a quantitative and qualitative in situ imaging approach was used on paraffin tissue liver sections.ResultsWe first demonstrated that polyploid hepatocytes are the major components of human liver parenchyma, polyploidy being mainly cellular (binuclear hepatocytes). Across liver lobules, polyploid hepatocytes do not exhibit a specific zonation pattern. During liver tumorigenesis, cellular ploidy is drastically reduced; binuclear polyploid hepatocytes are barely present in HCC tumours. Remarkably, nuclear ploidy is specifically amplified in HCC tumours. In fact, nuclear ploidy is amplified in HCCs harbouring a low degree of differentiation and TP53 mutations. Finally, our results demonstrated that highly polyploid tumours are associated with a poor prognosis.ConclusionsOur results underline the importance of quantification of cellular and nuclear ploidy spectra during HCC tumorigenesis.

Highlights d PKCl/i levels negatively correlate with HCC histological tumor grade d PKCl/i-deficient hepatocytes promote HCC linked to increased ROS and NRF2 activation d PKCl/i represses autophagy directly and inhibits OXPHOS to restrain ROS and NRF2 d Increased ROS and NRF2 by PKCl/i deficiency accounts for increased HCC

SUMMARY Serrated adenocarcinoma, an alternative pathway for colorectal cancer (CRC) development, accounts for 15–30% of all CRCs and is aggressive and treatment-resistant. We show that the expression of atypical protein kinase c (PKC)ζ and PKC λ/ι was reduced in human serrated tumors. Simultaneous inactivation of these genes in the mouse intestinal epithelium resulted in spontaneous serrated tumorigenesis that progressed to advanced cancer with a strongly reactive and immunosuppressive stroma. Whereas epithelial PKCλ/ι deficiency led to immunogenic cell death and the infiltration of CD8+ T cells, which repressed tumor initiation, PKCζ loss impaired interferon and CD8+ T cell responses, which resulted in tumorigenesis. Combined treatment with a TGF-β receptor inhibitor plus anti-PDL1 checkpoint blockade showed synergistic curative activity. Analysis of human samples supported the relevance of these kinases in the immunosurveillance defects of human serrated CRC. These findings provide insight into avenues for the detection and treatment of this poor-prognosis subtype of CRC.

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our findings have demonstrated that LECT2 is an key player of liver tumorigenesis as its absence reshapes the TME and the tumor phenotype revealing LECT2 as a promising immunotherapeutic option for HCC. This article is protected by copyright. All rights reserved.