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Review
. 2022 Oct 17;12(10):1503.
doi: 10.3390/biom12101503.

Pancreatic Cancer Research beyond DNA Mutations

Hiromichi Sato  1   2 , Kazuki Sasaki  1   2 , Tomoaki Hara  1 , Yoshiko Tsuji  1 , Yasuko Arao  1 , Chihiro Otsuka  1 , Yumiko Hamano  1 , Mirei Ogita  1 , Shogo Kobayashi  2 , Eric di Luccio  3 , Takaaki Hirotsu  3 , Yuichiro Doki  2 , Hidetoshi Eguchi  2 , Taroh Satoh  2 , Shizuka Uchida  4 , Hideshi Ishii  1
Affiliations
Review

Pancreatic Cancer Research beyond DNA Mutations

Hiromichi Sato et al. Biomolecules. .

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is caused by genetic mutations in four genes: KRAS proto-oncogene and GTPase (KRAS), tumor protein P53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A), and mothers against decapentaplegic homolog 4 (SMAD4), also called the big 4. The changes in tumors are very complex, making their characterization in the early stages challenging. Therefore, the development of innovative therapeutic approaches is desirable. The key to overcoming PDAC is diagnosing it in the early stages. Therefore, recent studies have investigated the multifaced characteristics of PDAC, which includes cancer cell metabolism, mesenchymal cells including cancer-associated fibroblasts and immune cells, and metagenomics, which extend to characterize various biomolecules including RNAs and volatile organic compounds. Various alterations in the KRAS-dependent as well as KRAS-independent pathways are involved in the refractoriness of PDAC. The optimal combination of these new technologies is expected to help treat intractable pancreatic cancer.

Keywords: RNA; cancer metabolism; mutations; pancreatic ductal adenocarcinoma; sequencing.

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Conflict of interest statement

Partial institutional endowments were received from Taiho Pharmaceutical Co., Ltd. (Tokyo, Japan), Hirotsu Bio Science Inc. (Tokyo, Japan); Kinshu-kai Medical Corporation (Osaka, Japan); Kyowa-kai Medical Corporation (Osaka, Japan); IDEA Consultants Inc. (Tokyo, Japan); Unitech Co. Ltd. (Chiba, Japan). E.d.L. is an employee and T.Hi is the CEO of Hirotsu Bio Science Inc. S.U. is a guest editor of this special issue of the journal.

Figures

Figure 1
Figure 1
Biopsy procedure for precision therapy against pancreatic ductal adenocarcinoma (PDAC). The characteristics of tumors can be obtained by liquid and solid biopsy. Blood sampling and needle biopsy are performed to obtain liquid samples, whereas surgery, endoscopic approach, and needle biopsy, in some cases, are conducted to examine solid samples. The information obtained from liquid and solid biopsies will contribute to precision medicine. A multifaceted approach may improve patient prognosis in intractable cancers (e.g., PDAC).
Figure 2
Figure 2
Multimodality approaches to diagnose and monitor pancreatic ductal adenocarcinoma (PDAC). Although various methods have been developed, no biomarker or PDAC diagnosis using only one method has been identified. The current situation is to increase the sensitivity and specificity by combining multiple methods. ctDNA, Circulating tumor DNA; UC, uncharacterized.
Figure 3
Figure 3
The mechanism by which KRAS proto-oncogene and GTPase (KRAS) mutations affect downstream signaling in the pancreatic ductal adenocarcinoma (PDAC). KRAS, KRAS Proto-Oncogene and GTPase; PI3Kl, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PIP2, phosphatidylinositol-4, 5-bisphosphate; PIP3, phosphatidylinositol-3, 4, 5-triphosphate; AKT, v-Akt murine thymoma viral oncogene homolog 1; mTOR, mechanistic target of rapamycin kinase. Under the control of KRAS, PI3 kinases catalyze the production of PIP3 by PIP2, although the downstream of mTOR has been studied for complete understanding.
Figure 4
Figure 4
KRAS proto-oncogene and GTPase (KRAS) and oncogene V-myc avian myelocytomatosis viral oncogene homolog (c-MYC)-dependent glycolysis in pancreatic ductal adenocarcinoma (PDAC). c-MYC, oncogene V-myc avian myelocytomatosis viral oncogene homolog; glucose-6-P, glucose-6-phosphate; LDH-A, lactate dehydrogenase A subunit.
Figure 5
Figure 5
KRAS proto-oncogene and GTPase (KRAS)-dependent alterations of TCA metabolism in pancreatic ductal adenocarcinoma (PDAC). TCA, tricarboxylic acid.
Figure 6
Figure 6
KRAS proto-oncogene and GTPase (KRAS)-dependent fueling serine and glycine metabolism in pancreatic ductal adenocarcinoma (PDAC). PHGDH, D-3-phosphoglycerate dehydrogenase; EGFR, epidermal growth factor receptor.
Figure 7
Figure 7
Competition of immune cells for nutrition in pancreatic ductal adenocarcinoma (PDAC). It has been suggested that some cancer cells are dependent on methionine (Hoffman effect). In the tumor microenvironment (TME), cancer cells are supposed to compete for methionine. SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine.
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