Vinicius Kannen

PARP7 is a member of the ADP-ribosyltransferase diphtheria toxin-like (ARTD) family and acts as a repressor of type I interferon (IFN) signaling. PARP7 inhibition causes tumor regression by enhancing antitumor immunity, which is dependent on the stimulator of interferon genes (STING) pathway, TANK-binding kinase 1 (TBK1) activity, and cytotoxic CD8⁺ T cells. To better understand PARP7′s role in cancer, we generated and characterized PARP7 knockout (Parp7^KO) EO771 mouse mammary cancer cells in vitro and in a preclinical syngeneic tumor model using catalytic mutant Parp7^H532A mice. Loss of PARP7 expression or inhibition of its activity increased type I IFN signaling, as well as the levels of interferon-stimulated gene factor 3 (ISGF3) and specifically unphosphorylated-ISGF3 regulated target genes. This was partly because PARP7′s modification of the RelA subunit of nuclear factor κ-B (NF-κB). PARP7 loss had no effect on tumor growth in immunodeficient mice. In contrast, injection of wildtype cells into Parp7^H532A mice resulted in smaller tumors compared with cells injected into Parp7^+/+ mice. Parp7^H532A mice injected with Parp7^KO cells failed to develop tumors and those that developed regressed. Our data highlight the importance of PARP7 in the immune cells and further support targeting PARP7 for anticancer therapy.

Background Colorectal cancer (CRC) has a high mortality rate and can develop in either colitis-dependent (colitis-associated (CA)-CRC) or colitis-independent (sporadic (s)CRC) manner. There has been a significant debate about whether mast cells (MCs) promote or inhibit the development of CRC. Herein we investigated MC activity throughout the multistepped development of CRC in both human patients and animal models. Methods We analyzed human patient matched samples of healthy colon vs CRC tissue alongside conducting a The Cancer Genome Atlas-based immunogenomic analysis and multiple experiments employing genetically engineered mouse (GEM) models. Results Analyzing human CRC samples revealed that MCs can be active or inactive in this disease. An activated MC population decreased the number of tumor-residing CD8 T cells. In mice, MC deficiency decreased the development of CA-CRC lesions, while it increased the density of tumor-based CD8 infiltration. Furthermore, co-culture experiments revealed that tumor-primed MCs promote apoptosis in CRC cells. In MC-deficient mice, we found that MCs inhibited the development of sCRC lesions. Further exploration of this with several GEM models confirmed that different immune responses alter and are altered by MC activity, which directly alters colon tumorigenesis. Since rescuing MC activity with bone marrow transplantation in MC-deficient mice or pharmacologically inhibiting MC effects impacts the development of sCRC lesions, we explored its therapeutic potential against CRC. MC activity promoted CRC cell engraftment by inhibiting CD8+ cell infiltration in tumors, pharmacologically blocking it inhibits the ability of allograft tumors to develop. This therapeutic strategy potentiated the cytotoxic activity of fluorouracil chemotherapy. Conclusion Therefore, we suggest that MCs have a dual role throughout CRC development and are potential druggable targets against this disease.

Background Previous data have reported that the growth of established tumors may be facilitated by postsepsis disorder through changes in the microenvironment and immune dysfunction. However, the influence of postsepsis disorder in initial carcinogenesis remains elusive. Methods In the present work, the effect of postsepsis on inflammation-induced early carcinogenesis was evaluated in an experimental model of colitis-associated colorectal cancer (CAC). We also analyzed the frequency and role of intestinal T regulatory cells (Treg) in CAC carcinogenesis. Results The colitis grade and the tumor development rate were evaluated postmortem or in vivo through serial colonoscopies. Sepsis-surviving mice (SSM) presented with a lower colonic DNA damage, polyp incidence, reduced tumor load, and milder colitis than their sham-operated counterparts. Ablating Treg led to restoration of the ability to develop colitis and tumor polyps in the SSM, in a similar fashion to that in the sham-operated mice. On the other hand, the growth of subcutaneously inoculated MC38luc colorectal cancer cells or previously established chemical CAC tumors was increased in SSM. Conclusion Our results provide evidence that postsepsis disorder has a dual effect in cancer development, inhibiting inflammation-induced early carcinogenesis in a Treg-dependent manner, while increasing the growth of previously established tumors.

Purpose: Brazil is the largest country in South America. Although a developing nation, birth rates have been decreasing in the last few decades, while its overall population is undergoing lifestyle changes and ageing significantly. Moreover, Brazil has had increasingly high mortality rates related to colorectal cancer (CRC). Herein, we investigated whether the Brazilian population is exhibiting increasing mortality rates related to colon cancer (CC) or rectal cancer (RC) in recent years.Methods: We examined data from the Brazilian Federal Government from 1979 to 2015 to determine whether CRC mortality and the population ageing process may be associated.Results: Our mathematical modelling suggests that mortality rates related to CC and RC events in the Brazilian population may increase by 79% and 66% in the next 24 years, respectively. This finding led us to explore the mortality rates for both diseases in the country, and we observed that the highest levels were in the south and southeast regions from the year 2000 onwards. CC events appear to decrease life expectancy among people during their second decade of life in recent years, whereas RC events induced decreases in life expectancy in those aged >30 years. Additionally, both CC and RC events seem to promote significant mortality rates in the male population aged > 60 years and living in the southern states.Conclusion: Our dataset suggests that both CC and RC events may lead to a significantly increasing number of deaths in the Brazilian male population in coming years.

Serotonin (5‐HT) signaling pathways are thought to be involved in colorectal tumorigenesis (CRT), but the role of 5‐HT synthesis in the early steps of this process is presently unknown. In this study, we used carcinogen treatment in the tryptophan hydroxylase 1 knockout (Tph1KO) and transgenic (Tph1^fl/flVillin^Cre) mouse models defective in 5‐HT synthesis to investigate the early mutagenic events associated with CRT. Our observations of the colonic crypt post‐treatment followed a timeline designed to understand how disruption of 5‐HT synthesis affects the initial steps leading to CRT. We found Tph1KO mice had decreased development of both allograft tumors and colitis‐related CRT. Interestingly, carcinogenic exposure alone induced multiple colon tumors and increased cyclooxygenase‐2 (Ptgs2) expression in Tph1KO mice. Deletion of interleukin 6 (Il6) in Tph1KO mice confirmed that inflammation was a part of the process. 5‐HT deficiency increased colonic DNA damage but inhibited genetic repair of specific carcinogen‐related damage, leading to CRT‐related inflammatory reactions and dysplasia. To validate a secondary effect of 5‐HT deficiency on another DNA repair pathway, we exposed Tph1KO mice to ionizing radiation and found an increase in DNA damage associated with reduced levels of ataxia telangiectasia and Rad3 related (Atr) gene expression in colonocytes. Restoring 5‐HT levels with 5‐hydroxytryptophan treatment decreased levels of DNA damage and increased Atr expression. Analysis of Tph1^fl/flVillin^Cre mice with intestine‐specific loss of 5‐HT synthesis confirmed that DNA repair was tissue specific. In this study, we report a novel protective role for 5‐HT synthesis that promotes DNA repair activity during the early stages of colorectal carcinogenesis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Experimental denervation of organs plays a key role in understanding the functional aspects of the normal innervation as well as the diseases related to them. In 1978 the experimental model of myenteric denervation of the rat gut by serosal application of benzalkonium chloride (BAC) was proposed. BAC is a positively charged surface-active alkylamine and is a powerful cationic detergent, which destroys bacteria after ionic attraction and for this reason is largely used as a surgical antiseptic. Since its initial report, the BAC-induced myenteric denervation model has been used to study many functional and pathological aspects of the enteric nervous system. So far this is the only pure method of myenteric denervation available for research in this area. Promising reports in the literature have shed light on the possibilities for the development of new uses of the BAC-denervation experimental model as a therapeutic tool in some pathological situations. This review aims to shed light on the main historical and recent findings provided by this experimental model.