From inflammation to cancer: the role of promyelocytic leukemia protein (PML)

The present doctoral project aimed to elucidate the function of PML in chronic inflammation and its impact on inflammation-driven tumorigenesis by using two models of inflammation: obesity and gastrointestinal tract inflammation. Our data firstly showed that PML-deficient (PML-/-) mice exhibited elevated IL-1β secretion in visceral adipose and colon tissues following pro-inflammatory stimuli, indicating that PML loss alone predisposes tissues to a heightened inflammatory state. Reversing the system, the obesity condition and colonic inflammation establishment, displayed a reduced PML expression in inflamed tissues, accompanied by enhanced cytokine release, suggesting the modulation of the protein from the environment 6,9. In fact, also orthotopically inoculating MC38cytLUC colorectal cancer cells into PML-/- mice, an accelerated tumor growth, increased tumor mass, and higher systemic levels of pro-inflammatory cytokines were observed. In this contest, cells derived from PML-deficient hosts exhibited increased proliferation and migration in vitro, confirming a persistent imprint of the hyperinflammatory environment. Similarly, syngeneic PML-/- colorectal cancer cells formed more aggressive tumors even in WT hosts, highlighting the effects of PML loss. Translation to human studies confirmed these observations. Visceral adipose tissue (AT) from obese women exhibited reduced PML expression and elevated IL-1β levels, inversely correlated with BMI. In colorectal cancer patients, tumor tissues showed higher pro-inflammatory cytokine expression and marked PML downregulation compared with matched healthy tissues. Overall, both murine models and human samples demonstrate that sustained inflammation is associated with PML downregulation, which contributes to tumor development and progression. Thus, PML reveal itself as a key mediator of chronic inflammation-driven tumorigenesis and its therapeutic modulation may represent a promising strategy to mitigate inflammation-associated disease and cancer progression.

Over the past years, inflammation is increasingly recognized as a major contributor to disease development, particularly in the context of modern lifestyle factors such as chronic stress, tobacco use, and obesity, which exacerbate pathological triggers. Nonetheless, while acute inflammation serves as a protective response to external and internal insults, if prolonged and unresolved it promotes immunosuppression, genetic instability, and tumor progression1–3. Within this contest, promyelocytic leukemia protein (PML) has emerged as a central regulator of inflammatory signaling4,5. Notably, PML at ER-MAMs forms a complex with NLRP3 and P2X7R receptor, counteracting P2X7R-mediated NLRP3 activation. Thus, loss of PML in the tumor microenvironment enhances NLRP3-driven inflammation, promoting tumorigenesis and worsening prognosis 6–8. Nonetheless, the role of PML in chronic inflammation and tissue-specific inflammatory responses remains to be deepened. The present doctoral project aimed to elucidate the function of PML in chronic inflammation and its impact on inflammation-driven tumorigenesis by using two models of inflammation: obesity and gastrointestinal tract inflammation. Our data firstly showed that PML-deficient (PML-/-) mice exhibited elevated IL-1β secretion in visceral adipose and colon tissues following pro-inflammatory stimuli, indicating that PML loss alone predisposes tissues to a heightened inflammatory state. Reversing the system, the obesity condition and colonic inflammation establishment, displayed a reduced PML expression in inflamed tissues, accompanied by enhanced cytokine release, suggesting the modulation of the protein from the environment 6,9. In fact, also orthotopically inoculating MC38cytLUC colorectal cancer cells into PML-/- mice, an accelerated tumor growth, increased tumor mass, and higher systemic levels of pro-inflammatory cytokines were observed. In this contest, cells derived from PML-deficient hosts exhibited increased proliferation and migration in vitro, confirming a persistent imprint of the hyperinflammatory environment. Similarly, syngeneic PML-/- colorectal cancer cells formed more aggressive tumors even in WT hosts, highlighting the effects of PML loss. Translation to human studies confirmed these observations. Visceral adipose tissue (AT) from obese women exhibited reduced PML expression and elevated IL-1β levels, inversely correlated with BMI. In colorectal cancer patients, tumor tissues showed higher pro-inflammatory cytokine expression and marked PML downregulation compared with matched healthy tissues. Overall, both murine models and human samples demonstrate that sustained inflammation is associated with PML downregulation, which contributes to tumor development and progression. Thus, PML reveal itself as a key mediator of chronic inflammation-driven tumorigenesis and its therapeutic modulation may represent a promising strategy to mitigate inflammation-associated disease and cancer progression.