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Activated KRAS, polyamines, iASPP and TME: a multiple liaison in pancreatic cancer

Cell Death & Differentiation volume 30, pages 1615–1617 (2023)Cite this article

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The treatment of pancreatic ductal adenocarcinoma (PDAC) is one of the most unmet clinical needs in oncology. Indeed, PDAC is the most common and lethal malignancy of pancreatic cancer with a 5-year survival rate under 5%. The majority of cases are unresectable and combined systemic therapy is offered as a palliative option. PDAC-related mortality is expected to surpass breast and colorectal cancers by 2030, making PDAC one of the malignancies with the greatest number of unfulfilled needs for innovative therapy [1]. PDAC tumors are characterized by a high degree of fibrosis, believed to be a major contributor to their therapy resistance. Besides KRAS mutations that appear to occur at early stages, TP53 mutations are strongly associated with poor outcome [2,3,4,5]. A recent phase III adjuvant trial using gemcitabine has shown that TP53 mutations were a negative prognostic factor for disease-free survival in untreated patients. Interestingly, they were a positive predictive factor for gemcitabine efficacy [6]. These observations suggest that TP53 mutation status and targeting may inform improved personalized therapy strategies in PDAC patients [7,8,9,10].

In the present issue of Cell Death and Differentiation, Lu’s group together with her collaborators elegantly unveil a new role of iASPP, a wt-p53 suppressor [12], which exerts anti-inflammatory and tumor suppressor activities on KRAS G12D-induced or KRAS G12D/mutant P53R172H PC onset. Indeed, iASPP depletion in vivo favors inflammation, acinar to ductal metaplasia and PDAC insurgence [13]. Notably, either iASPP deletion or p53 mutations affect overlapping gene patterns that include NFkB and AP1 transcriptional-regulated inflammatory genes thereby providing molecular insights for the iASPP anti-inflammatory and tumor suppressor activities on PDAC onset (Fig. 1). Interestingly, higher levels of iASPP transcript are associated with good prognosis of PC patients. As PDAC TME appears to be critical for its aggressive malignancy as well as its refractoriness to standard anticancer therapies, Lu’s group along with his collaborators investigated the impact of iASPP’s inflammatory role of shaping the TME of both KRAS G12D and KRASG12G/mutant P53R172H in vivo models. Upon iASPP depletion, they found aberrant production of pro-tumorigenic cytokines such as GM-CSF, CCL2, CCL5, IL1-α and IL1-β and other inflammatory factors. This effect was paired with an increased infiltration of B, CD4, CD8 and Treg cells, consequently framing the pro-tumorigenic cytokine release into a rewired and permissive immune landscape. iASPP anti-inflammatory activity exhibited pancreatic tissue specificity, thus reinforcing its critical role as a pancreatic tumor suppressor gene.

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Fig. 1: Reciprocal cross-talk between RAS mutations in PDAC cells and the surrounding TME.

References

  1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–21.

    Article  CAS  PubMed  Google Scholar 

  2. Levine AJ. Exploring the future of research in the Tp53 field. Cell Death Differ. 2022;29:893–4.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Barnett AH, Pyke DA. The genetics of diabetic complications. Clin Endocrinol Metab. 1986;15:715–26.

    Article  CAS  PubMed  Google Scholar 

  4. Butera A, Roy M, Zampieri C, Mammarella E, Panatta E, Melino G, et al. p53-driven lipidome influences non-cell-autonomous lysophospholipids in pancreatic cancer. Biol Direct. 2022;17:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Blandino G. Drugging THE MASTER REGulator TP53 in cancer: mission possible? J Clin Oncol. 2021;39:1595–7.

    Article  CAS  PubMed  Google Scholar 

  6. Sinn M, Sinn BV, Treue D, Keilholz U, Damm F, Schmuck R, et al. TP53 mutations predict sensitivity to adjuvant gemcitabine in patients with pancreatic ductal adenocarcinoma: next-generation sequencing results from the CONKO-001 Trial. Clin Cancer Res. 2020;26:3732–9.

    Article  CAS  PubMed  Google Scholar 

  7. Panatta E, Zampieri C, Melino G, Amelio I. Understanding p53 tumour suppressor network. Biol Direct. 2021;16:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Thomas AF, Kelly GL, Strasser A. Of the many cellular responses activated by TP53, which ones are critical for tumour suppression? Cell Death Differ. 2022;29:961–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mammarella E, Zampieri C, Panatta E, Melino G, Amelio I. NUAK2 and RCan2 participate in the p53 mutant pro-tumorigenic network. Biol Direct. 2021;16:11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Voutsadakis IA. Mutations of p53 associated with pancreatic cancer and therapeutic implications. Ann Hepatobiliary Pancreat Surg. 2021;25:315–27.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lee MS, Dennis C, Naqvi I, Dailey L, Lorzadeh A, Ye G, et al. Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer. Nature. 2023;616:339–47.

    Article  CAS  PubMed  Google Scholar 

  12. Zheng S, Wang X, Liu H, Zhao D, Lin Q, Jiang Q, et al. iASPP suppression mediates terminal UPR and improves BRAF-inhibitor sensitivity of colon cancers. Cell Death Differ. 2023;30:327–40.

    Article  CAS  PubMed  Google Scholar 

  13. Miller P, Akama-Garren EH, Owen RP, Demetriou C, Carroll TM, Slee E, et al. p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation driven pancreatic cancer. Cell Death Differ. 2023, in press.

  14. Panatta E, Butera A, Celardo I, Leist M, Melino G, Amelio I. p53 regulates expression of nuclear envelope components in cancer cells. Biol Direct. 2022;17:38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Adiseshaiah PP, Crist RM, Hook SS, McNeil SE. Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer. Nat Rev Clin Oncol. 2016;13:750–65.

    Article  CAS  PubMed  Google Scholar 

  16. Agostini M, Mancini M, Candi E. Long non-coding RNAs affecting cell metabolism in cancer. Biol Direct. 2022;17:26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Aubrey BJ, Brennan MS, Diepstraten ST, Wang Z, Chang C, Herold MJ, et al. Loss of TRP53 reduces but does not overcome dependency of lymphoma cells on MCL-1. Cell Death Differ. 2022;29:1074–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Donzelli S, Cioce M, Sacconi A, Zanconato F, Daralioti T, Goeman F, et al. A PIK3CA-mutant breast cancer metastatic patient-derived organoid approach to evaluate alpelisib treatment for multiple secondary lesions. Mol Cancer. 2022;21:152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang Z, Strasser A, Kelly GL. Should mutant TP53 be targeted for cancer therapy? Cell Death Differ. 2022;29:911–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work has been supported by the MUR-PNRR M4C2I1.3 PE6 project PE00000019 Heal Italia (CUP: H83C22000550006) to GB.

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  1. Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome, 00144, Italy

    Giovanni Blandino

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Correspondence to Giovanni Blandino.

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Blandino, G. Activated KRAS, polyamines, iASPP and TME: a multiple liaison in pancreatic cancer. Cell Death Differ 30, 1615–1617 (2023). https://doi.org/10.1038/s41418-023-01169-2

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